3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors

ABSTRACT

This invention provides compounds of Formula (I), having the structurewhere T, Z, X, A, R&lt;1&gt;, R&lt;2a&gt;, R&lt;2b&gt;, R&lt;2c&gt;, R&lt;3&gt;, R&lt;4&gt;, and n are defined herein, or a pharmaceutically acceptable salt thereof which are useful as antineoplastic agents and in the treatment of osteoporosis and polycystic kidney disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.09/820,070, filed Mar. 28, 2001 now U.S. Pat. No. 6,521,618 which claimsbenefit of prior U.S. Provisional Application No. 60/219,322 which wasconverted from U.S. patent application Ser. No. 09/535,843 filed Mar.28, 2000, pursuant to a petition filed under 37 C.F.R. 1.53 (c)(2) filedAug. 2, 2000. These applications are herein incorporated by reference intheir entireties.

BACKGROUND OF INVENTION

1. Field of the Invention

This invention relates to 3-cyanoquinoline, 3-cyano-1,6-naphthyridineand 3-cyano-1,7-naphthyridine containing compounds as well as theirpharmaceutically acceptable salts. The compounds of the presentinvention inhibit the activity of protein kinases that are required forcell growth and differentiation. The compounds of this invention aretherefore useful for the treatment of certain diseases that result fromactivity of these protein kinases. The compounds of this invention areanti-cancer agents and are useful for the treatment of cancer inmammals. In addition, the compounds of this invention are useful for thetreatment of polycystic kidney disease in mammals. The compounds of thisinvention may also be used in the treatment of osteoporosis. Thisinvention also relates to the manufacture of said compounds, their usefor the treatment of cancer, polycystic kidney disease and osteoporosis,and the pharmaceutical preparations containing them.

2. Description of the Prior Art

Protein kinases are enzymes that catalyze the transfer of a phosphategroup from ATP to an amino acid residue, such as tyrosine, serine,threonine, or histidine on a protein. Regulation of these proteinkinases is essential for the control of a wide variety of cellularevents including proliferation and migration. Specific protein kinaseshave been implicated in diverse conditions including cancer [Traxler P.M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., EmergingDrugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med.5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995)],atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis[Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., NatureMedicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90,1622 (1992).

Tyrosine kinases (TKs) are divided into two classes: thenon-transmembrane TKs and transmembrane growth factor receptor TKs(RTKs). Growth factors, such as epidermal growth factor (EGF), bind tothe extracellular domain of their partner RTK on the cell surface whichactivates the RTK, initiating a signal transduction cascade thatcontrols a wide variety of cellular responses including proliferationand migration. The overexpession of EGF and also of members of theepidermal growth factor receptor (ECFr) family, which includes EGF-r,erbB-2, erbB-3 and erbB-4, is implicated in the development andprogression of cancer [Rusch, V., Cytokine Growth Factor Rev., 7, 133(1996), Davies, D. E., Biochem. Pharmacol., 51, 1101 (1996) andModjtahedi, E., Int. J. Oncol., 4, 277 (1994)]. Specifically, overexpression of the receptor kinase product of the erbB-2 oncogene hasbeen associated with human breast and ovarian cancers [Slamon, D. J.,Science, 244, 707 (1989) and Slamon, D. J. Science, 235, 177 (1987)].Upregulation of EGFr kinase activity has been associated with epidermoidtumors [Reiss, M., Cancer Res., 51, 6254 (1991)], breast tumors [Macias,A., Anticancer Res., 7, 459 (1987)], and tumors involving other majororgans [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)].

It is also known that deregulation of EGF receptors is a factor in thegrowth of epithelial cysts in the disease described as polycystic kidneydisease [Du, J., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J.,Pediatric Res., 37(6), 755 (1995); Gattone, V. H., DevelopmentalBiology, 169(2), 504 (1995); Wilson, P. D., Eur. J. Cell Biol., 61(1),131, (1993)]. Compounds which inhibit the catalytic function of the EGFreceptors, may consequently be useful for the treatment of this disease.

In addition to EGFr, there are several other RTKs including FGFr, thereceptor for fibroblast growth factor (FGF); flk-1, also known as KDR,and flt-1, the receptors for vascular endothelial growth factor (VEGF);and PDGFr, the receptor for platelet derived growth factor (PDGF). Theformation of new blood vessels, a process known as angiogenesis, isessential for tumor growth. Two natural angiogenesis inhibitors,angiostatin and endostatin, dramatically inhibited the growth of avariety of solid tumors. [O'Reilly, M. S., Cell, 79, 315 (1994)];O'Reilly, M. S., Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell,88, 277 (1997)]. Since FCF and VEGF are known to stimulate angiogenesis,inhibition of the kinase activity of their receptors should block theangiogenic effects of these growth factors. In addition, the receptortyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis[Sato, T. N., Nature, 376, 70 (1995)]. Compounds that inhibit the kinaseactivity of FGFr, flk-1, flt-1, tie-1 or, tie-2 may inhibit tumor growthby their effect on angiogenesis.

PDGF is a potent growth factor and chemoattractant for smooth musclecells (SMCs) and the renarrowing of coronary arteries followingangioplasty is due in part to the enhanced proliferation of SMCs inresponse to increased levels of PDGF. Therefore, compounds that inhibitthe kinase activity of PDGFr may be useful in the treatment ofrestenosis. In addition, since PDGF and PDGFr are overexpessed inseveral types of human gliomas, small molecules capable of suppessingPDGFr activity, have potential utility as anticancer therapeutics[Nister, M., J. Biol. Clem. 266, 16755 (1991); Strawn, L. M., J. Biol.Chem. 269, 21215 (1994)].

Other RTKs that could potentially be inhibited by compounds of thisinvention include colony stimulating factor receptor, the nerve growthfactor receptors (trkA, trkB and trkC), the insulin receptor, theinsulin-like growth factor receptor, the hepatocyte growth factorreceptor and the erythiopoietin-producing hepatic cell receptor (EPH).

In addition to the RTKs there is another family of TKs termed thecytoplasmic protein or non-receptor TKs. The cytoplasmic protein TKshave intrinsic kinase activity, are present in the cytoplasm andnucleus, and participate in diverse signaling pathways. There are alarge number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70and Csk. However, the major family of cytoplasmic protein TKs is the Srcfamily which consists of at least eight members (Src, Fyn, Lyn, Yes,Lck, Fgr, Hck and Blk) that participate in a variety of signalingpathways [Schwartzberg, P. L., Oncogene, 17, 1463 (1998)]. Theprototypical member of this tyrosine kinase family is Src, which isinvolved in proliferation and migration responses in many cell types.Src activity has been shown to be elevated in breast, colon (˜90%),pancreatic (>90%) and liver (>90%) tumors. Greatly increased Srcactivity is also associated with metastasis (>90%) and poor prognosis.Antisense Src message impedes growth of colon tumor cells in nude mice[Staley, C. A., Cell Growth Differentiation, 8, 269 (1997)], suggestingthat Src inhibitors should slow tumor growth. In addition to its role incell proliferation, Src also acts in stress response pathways, includingthe hypoxia response. Nude mice studies with colon tumor cellsexpressing antisense Src message have reduced vascularization [Ellis, L.M., J. Biol. Chem., 273, 1052 (1998)], which suggests that Srcinhibitors would be anti-angiogenic as well as anti-proliferative.

In addition to its role in cancer, Src also appears to play a role inosteoporosis. Mice genetically engineered to be deficient in Srcproduction were found to exhibit osteopetiosis, the failure to resorbbone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin.,Invest., 90, 1622 (1992)]. This defect was characterized by a lack ofosteoclast activity. Since osteoclasts normally express high levels ofSrc, inhibition of Src kinase activity may be useful in the treatment ofosteoporosis [Missbach, M., Bone, 24, 437 (1999)].

Two members of the cytoplasmic protein TKs, lck and ZAP-70 arepredominately expressed on T-cells and natural killer (NK) cells.Inhibitors of these kinases can suppress the immune system and thereforehave possible therapeutic potential to treat autoimmune diseases such asrheumatoid arthritis, sepsis, and transplant rejection [Myers, M.,Current Pharm. Design, 3, 473 (1997)].

Besides TKs, there are additional kinases including those thatphosphorylate serine and/or threonine residues on proteins. A majorpathway in the cellular signal transduction cascade is themitogen-activated protein kinase (MAPK) pathway which consists of theMAP kinase kinases (MAPKK), including mek, and their substrates, the MAPkinases (MAPK), including erk [Seger, R., FASEB, 9, 726 (1995)]. Whenactivated by phosphorylation on two serine residues by upstream kinases,such as members of the raf family, mek catalyzes the phosphorylation ofthreonine and tyrosine residues on erk. The activated erk thenphosphorylates and activates both transcription factors in the nucleusand other cellular targets. Over-expression and/or over-activation ofmek or erk is associated with various human cancers [Sivaraman, V. S.,J. Clin. Invest., 99, 1478 (1997)].

As mentioned above, members of the raf family of kinases phosphorylateserine residues on mek. There are three serine/threonine kinase membersof the raf family known as a-raf, b-raf and c-raf. While mutations inthe raf genes are rare in human cancers, c-raf is activated by the rasoncogene which is mutated in a wide number of human tumors. Thereforeinhibition of the kinase activity of c-raf may provide a way to preventras medicated tumor growth [Campbell, S. L., Oncogene, 17, 1395 (1998)].

The cyclin-dependent kinases (cdks), including cdc2/cyclin B,cdk2/cyclin A, cdk2/cyclin E and cdk4/cyclin D, and others, areserine/threonine kinases that regulate mammalian cell division.Increased activity or activation of these kinases is associated with thedevelopment of human tumors [Garrett, M. D., Current Opin. GeneticsDevel., 9, 104 (1999); Webster, K. R., Exp. Opin. Invest. Drugs, 7, 865(1998)]. Additional serine/threonine kinases include the protein kinasesA, B, and C. These kinases, are known as PKA or cyclic AMP-dependentprotein kinase, PKB or Akt, and PKC, and all three play key roles insignal transduction pathways responsible for oncogenesis [Glazer, R. I.,Current Pharm. Design, 4(3), 277 (1998)]. Compounds capable ofinhibiting the kinase activity of mek, erk, raf, cdc2/cyclin B,cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D, PKA, Akt or PKC may beuseful in the treatment of diseases characterized by abnormal cellularproliferation, such as cancer.

The serine/threonine kinase UL97 is a virion-associated protein kinasewhich is required for the replication of human cytomegalovirus [Wolf, D.G., Arch. Virology 143(6), 1223 (1998) and He, Z., J. Virology, 71,405(1997)]. Compounds capable of inhibiting the kinase activity of UL97may be useful antiviral therapeutics. Since certain bacteria require theaction of a histidine kinase for proliferation [Loomis, W. F., J. CellSci. 110, 1141 (1997)], compounds capable of inhibiting such histidinekinase activity may be useful antibacterial agents.

Some 3-cyanoquinoline derivatives are inhibitors of tyrosine kinases andare described in the application WO9843960 (U.S. Pat. No. 6,002,008).These 3-cyanoquinolines may be substituted at carbon-5 through carbon-8with an unsubstituted phenyl, alkene or alkyne group. A 3-cyanoquinolinewith a 4-(2-methylanilino) substituent having gasitic (H⁺/K⁺)-ATPaseinhibitory activity at high concentrations has been described [Ife, R.,J. Med. Chem., 35(18) 3413 (1992)].

Some 3-cyanoquinolines are claimed as inhibitors of tumor necrosisfactor (TNF) or phosphodiesterase IV. The application WO982007 claims3-cyanoquinolines that may be unsubstituted at carbon-2 and substitutedat carbon-4 with an aryloxy, cycloalkoxy, heteroaryloxy or anilinogroup. However these compounds must contain at carbon-8 a hydroxy,thioalkyl, alkoxy of 1 to 6 carbon atoms or cycloalkoxy group optionallysubstituted with one or more halogens. These compounds must also containat carbon-5 an imidazole, oxazole, or thiazole ring attached to thequinoline ring at carbon-2 and this hereroaryl ring must be fused to a6-membered aromatic ring that may contain 1 or 2 nitrogen atoms in thering. The application WO9857936 also claims 3-cyanoquinolines asinhibitors of tumor necrosis factor (TNF) or phosphodiesterase IV. Thesecompounds may be unsubstituted at carbon-2 but must contain at carbon-8a hydroxy, thioalkyl, alkoxy of 1 to 6 carbon atoms or cycloalkoxy groupoptionally substituted with one or more halogens. These compounds mustcontain at carbon-5 an aryl or heteroaryl ring that may be substituted.In addition these compounds may contain a aryloxy, cycloalkoxy, orheteroaryloxy group at carbon-4. However when an amino group is presentat carbon-4 the amino group must be substituted by an alkylcarbonyl,alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl,arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or alkylsulfonylgroup.

The applications WO9744036 and WO9744322 claim additional3-cyanoquinolines as inhibitors of tumor necrosis factor (TNF) ofphosphodiesterase IV but these applications do not claim thesubstituents at carbon-5 through carbon-8 of the 3-cyanoquinolinesclaimed herein.

The applications WO9404526 and WO9404527 claim 3-cyanoquinolines aspesticides. These 3-cyanoquinolines may be unsubstituted at carbon-2,but differ from the compounds claimed herein that they must contain atcarbon-4 a group of formula —Y(CH₂)₂-phenyl, —Y(CH₂)₂-pyridine or—Y(CH₂)₂-pyridazine, where Y is O, CH₂, NH or N-alkyl. Theseapplications also do not claim the substituents at carbon-5 throughcarbon-8 of the 3-cyanoquinolines claimed herein.

A series of patent applications, WO9719927, WO9602509, and WO9532948claim 3-cyanoquinolines as neurokinin inhibitors. However thesecompounds must contain at carbon-4 of the quinoline a group of theformula C(X)NRR wherein X is O, S or N—CN and in addition carbon-2 ofthe quinoline can not be unsubstituted.

Several patents and patent applications claim 3-cyanoquinolines asinhibitors of leukotriene biosynthesis. While some of these, includingU.S. Pat. No. 5,232,916, U.S. Pat. No. 5,104,882, EP349062 andDE19532714, claim compounds with the substituents at carbon-4 and atcarbon-5 through carbon-8 of the cyanoquinoline claimed herein, all ofthe compounds must contain a substituent at carbon-2.

Several patent applications claim 3-cyanoquinolines as angiotensin IIantagonists. EP499415 claims 3-cyanoquinolines, unsubstituted atcarbon-2 and substituted at carbon-4 with a group of the formulaNRCH₂Ph, wherein R is H or lower, alkyl and Ph is phenyl which must besubstituted by a tetrazole, C(O)NHtetrazole or other specified groups.This application does not claim the substituents at carbon-5 throughcarbon-8 of the 3-cyanoquinolines claimed herein. A series of patentapplications EP527534, EP156442 and CB2264710 claim 3-cyanoquinolines,unsubstituted at carbon-2 and substituted at carbon-4 with a group ofthe formula OCH₂Ph, but these applications do not claim the substituentsat carbon-5 through carbons-8 of the 3-cyanoquinolines claimed herein.

U.S. Pat. No. 5,480,883 describes a series of compounds includingquinolines as tyrosine kinase inhibitors. These quinoline compounds areunsubstituted at carbon-3. Patent application WO9609294 describesquinazolines and quinolines substituted at carbon-4 by anilino, phenoxyand thiophenoxy groups as tyrosine kinase inhibitors, however thequinoline compounds are unsubstituted at carbon-3. U.S. Pat. No.5,650,415 describes quinolines substituted at carbon-4 by a benzylaminoor benzylthio group as tyrosine kinase inhibitors. These quinolineshowever must contain an ethyl ester group at carbon-3. Additionalquinoline compounds substituted with an ethyl ester at carbon-3 and ananilino group at carbon-4 are claimed in U.S. Pat. No. 4,343,804 asantisecretory and antiulcer compounds.

Patent application WO9813350 describes 3-fluoroquinolines, quinolines,1,6-naphthyridines and 1,7-naphthyridines substituted at carbon-4 byanilino, phenoxy and thiophenoxy groups as tyrosine kinase inhibitors,but does not include the 3-cyano group contained in the quinoline,1,6-naphthyridine and 1,7-naphthyridine compounds of the presentinvention.

Several patents and patent applications disclose quinazolines withanilino groups it carbon-4 and substituted at carbons-5 to 8 with aphenyl, naphthyl, alkene, alkyne or a 5-6 membered heteroaryl group askinase inhibitors. U.S. Pat. No. 5,814,630 describes quinazolinessubstituted at carbon-7 with a phenyl, naphthyl or 5-6 memberedheteroaromatic ring. U.S. Pat. No. 5,866,572 describes4-anilinoquinazolines substituted at carbon-6 with a phenyl, naphthyl or5-6 membered heteroaryl group that may be directly attached to thequinoline or attached via a carbonyl, alkyl or hydroxymethylene linker.U.S. Pat. No. 5,955,464 describes 4-anilinoquinazolines substituted atcarbon-6 by a nitrogen containing heteroaryl group that is linked to thequinazoline via a nitrogen atom. The application EP837063 describesquinazolines that are substituted at carbons-5 to 8 with one or moreoptionally substituted 5- or 6-membered heteroaryl, or phenyl ringseither directly attached to the quinazoline or attached via an alkene oralkyne linker.

Additionally, the application WO98024134 describes quinazolines andquinolines, as kinase inhibitors, unsubstituted at carbon-3, that aresubstituted at carbons-5 to 8 with one or more optionally substituted 5-or 6-membered heteroalyl or phenyl rings. Patent applications WO9802437and WO9935146 further describe ring systems, including quinolines,1,6-naphthyridines and 1.7-naphthyridines with anilino groups atcarbon-4 and substituted at carbons-5 to 8 with one or more optionallysubstituted 5- or 6-membered heteroaryl or phenyl rings, as kinaseinhibitors and which do not disclose the 3-cyano group of the presentinvention.

The compounds of the present invention are 3-cyanoquinolines with asuitably substituted heteroaryl, bicyclic heteroaryl, aryl, alkene oralkyne group at carbon-5, carbon-6, carbon-7, or carbon-8. Alternativenames for 3-cyanoquinolines include 3-quinolinecarbonitriles andquinoline-3-carbonitriles. Also included in the present invention, are3-cyano-1,6-naphthyridines with a suitably substituted heteroaryl,bicyclic heteroaryl, alkene or alklyne group at carbon-5, carbon-7, orcarbon-8 and 3-cyano-1,7-naphthyridines with a suitably substitutedheteroaryl, bicyclic heteroaryl, aryl, alkene or alkyne group atcarbon-5, carbon-6, or carbon-8. The compounds of the present inventioninhibit the activity of protein kinases that are required for cellgrowth and differentiation and are therefore useful for the treatment ofcertain diseases that result from activity of these protein kinases. Thecompounds of this invention are anti-cancer agents and are useful forthe treatment of cancer in mammals. Further, the compounds of thisinvention are useful for the treatment of polycystic kidney disease inmammals.

SUMMARY OF THE INVENTION

In accordance with the present invention there is provided compoundsrepresented by Formula (I):

wherein:

X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—;

n is an integer of 0 or 1;

m is an integer of 0 to 2;

q is an integer of 0 to 5;

p is an integer of 2 to 5;

s is an integer of 0 to 5;

r is an integer of 0 to 5;

J is halogen;

A is —(C(R⁹)₂)_(r)—, —C(O)—, —C(O)(C(R⁹)₂)_(r)—, —(C(R⁹)₂)_(r)C(O)—,-cycloalkyl- or is absent;

T and Z are each independently carbon or N, provided that both T and Zare not simultaneously N;

R¹ is selected from a cycloalkyl ring of 3 to 10 carbon atoms,optionally substituted with one or more independently selected alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentindependently selected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH,—R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂,—NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH,—OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵,—OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H,—R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q,—R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups whereinY is independently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—,—NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—,—S(O)_(m)(C(R⁹)²)_(q)—, —NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—,—(C(R⁹)₂)_(q)(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—, —(C(R⁹)₂)_(q)S(O)_(m)—,—(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰, —C≡C—, cis and trans —CH═CH— andcycloalkyl of 3 to 10 carbon atoms;

a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteoatoms orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4heteroatoms which may be the same or different selected from N, O and Swherein the bicyclic heteroaryl ring system may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y isindependently selected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—,—NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—,—S(O)_(m)(C(R⁹)₂)_(q)—, NH(C(R⁹)₂)_(q), —NR¹⁰(C(R⁹)₂)_(q),—(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—, —(C(R⁹)₂)_(q)S(O)_(m)—,—(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cis and trans —CH═CH— andcycloalkyl of 3 to 10 carbon atoms; and a moiety of the formula

E is —NH—, —NR⁵—, —O—, —S(O)_(m)—, —C(O)—, —CH₂—, —CHR⁵— or —CR⁵R⁵—;

Q is —NR⁵R⁵ and further provided that when each R⁵ is independentlyselected from alkyl and alkenyl, R⁵R⁵ may optionally be taken togetherwith the nitrogen atom to which they are attached forming a heterocyclylring of 3 to 8 atoms, optionally containing 1 or 2 additionalheteroatoms which may be the same or different selected from N, O and S;

R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are each, independentlyselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH—, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —R¹¹, —OR¹¹, —NHR¹¹ and —R⁶OC(O)Q;

R^(2a), R^(2b), and R^(2c), are each, independently selected from —H,-aryl, —CH₂aryl, —Oaryl, —S(O)_(m), —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH,—CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH,—OR⁷OR⁵, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)R¹², —(C(R⁹)₂)_(q)R¹²,

G is —NH—, —NR¹⁰—, —O— of —S(O)_(m)—;

R³ is selected from alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹⁾ ₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰,—COR¹⁰—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰,—(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(q)OR¹⁰,—G(C(R⁹)₂₎ _(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atomsoptionally substituted with 1 to 4 substituents which may be the same ordifferent selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H—, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteoatoms or particularly 1 or 2 heteroatoms which may be the same ordifferent, selected from N, O and S where the heteroaryl ring may beoptionally substituted with to 4 substituents which may be the same ordifferent selected from R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹⁾₂)_(q)NH₂, —(C(R⁹)₂)_(q)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹² and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH;

R⁴ is selected from —(C(R⁹)₂)_(r)H, optionally substituted with one ormore of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H,—CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH;

alkenyl of 2 to 6 carbon atoms, optionally substituted with one or moreof —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H,—CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH;

alkynyl of 2 to 6 carbon atoms, optionally substituted with one or moreof —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H,—CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —Q(C(R⁹)₂)_(p)OH;

aryl of 6 to 12 carbon atoms optionally substituted wit 1 to 4substituents which may be the same or different selected from —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aheteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹¹, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(Q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(P)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH;

R⁵ is a monovalent group independently selected from alkyl of 1 to 12carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbonatoms, and alkynyl of 2 to 6 carbon atoms;

R⁶ is a divalent group selected from alkyl of 1 to 6 carbon atoms,alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;

R⁷ is a divalent alkyl group of 2 to 6 carbon atoms;

R⁸ is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally besubstituted with one or more alkyl groups of 1 to 6 carbon atoms; arylof 6 to 12 carbon atoms optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂,—N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q,—OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶C(O)R⁵, —R⁶C(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6 atoms containing 1 to 4heteroatoms or particularly 1 or 2 heteroatoms which may be the same ordifferent, selected from N, O and S wherein the heteroaryl ring may beoptionally substituted with 1 to 4 substituents which may be the same ordifferent selected from —H, -aryl, —CH₂aryl, —NHary, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷R⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —R⁶R¹²,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶C(O)R⁵, —R⁶OC(O)NH₂, —R⁶C(O)NHR⁵ and—R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q;

R⁹ is independently —H, —F or —R⁵;

R¹⁰ is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6carbon atoms;

R¹¹ is a cycloalkyl group of 3 to 10 carbon atoms;

R¹² is —N(O)_(n)R¹³R¹⁴ or —N⁺(R¹⁰R¹³R¹⁴)J⁻;

provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1, R¹³ or R¹⁴ are notH;

R¹³ and R¹⁴ are independently selected from a group consisting of —H,—R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵, —(C(R⁹)₂)_(q)heteroaryl-R¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷,—(C(R⁹)₂)_(p)S(O)_(m)R¹⁶, —(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶and—(C(R⁹)₂)_(p)C(O)R¹⁵; further provided that R³ and R¹⁴ may optionally betaken together with the nitrogen to which they are attached forming aheterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionallysubstituted on either nitrogen or carbon by one or more selected fromthe group, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;

R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroalyl, —(C(R⁹)₂)_(q)hetetocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰, —(C(R⁹)₂)_(q)CO₂R¹⁰,—(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(q)COR¹⁰,(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂;

R¹⁶ and R¹⁷ are independently selected from n group consisting of —H,—R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl,—(C(R⁹)₂)_(q)heterocyclyl, —(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰,—(C(R⁹)₂)_(p)NH₂, —(C(R⁹)₂)_(p)NHR₂, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰,—(C(R⁹)₂)_(p)S(O)_(m)R¹⁰, —(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰,—(C(R⁹)₂)_(p)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and—(C(R⁹)₂)_(p)CONH₂;

R¹⁸ is independently selected from the group consisting of —H, -aryl,—R⁵, —R⁶NH₂, —R⁶NHR⁵ and —R⁶Q;

provided that, when T and Z are carbon, A is absent, r is 0 and R⁴ is—(C(R⁹)₂)_(r)H, then,

a. R³ is not unsubstituted thiophene, furan, thiazole, imidazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl oralkynyl; or

b. R³ is not monosubstituted by —R¹⁰, —(C(R⁹)₂)_(q)OH, or—(C(R⁹)₂)_(q)OR¹⁰ when R³ is thiophene, furan, thiazole, imidazole,1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine; and

c. R¹³ and R¹⁴ are not alkyl of 1 to 6 carbon atoms when R³ isthiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole or pyridine when R³ is substituted by —(C(R⁹)₂)_(s)R¹² and R¹²is —NR¹³R¹⁴;

further provided that, when T and Z are carbon, A is absent and R⁴ isphenyl, then,

a. R⁴ is not substituted by —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)Jor —(C(R⁹)₂)_(q)NH₂ or unsubstituted when R³ is thiophene, furan,thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole orpyridine; and

b. R¹³ and R¹⁴ are not independently alkyl of 1 to 3 carbon atoms whenR³ is thiophene, furan, thiazole, imidazole, 1,2,3-triazole,1,2,4-triazole, tetrazole or pyridine, wherein R⁴ is substituted by—(C(R⁹)₂)_(s)R¹² and s is 0 and R¹² is —NR¹³R¹⁴;

additionally provided that, when T and Z are carbon, then,

a. carbon-8 is not substituted by —OH, —OR¹⁰, —SR¹⁰, or —OR¹¹ whencarbon-5 is substituted by an imidazole, oxazole or thiazole ring thatis fused to a 6-membered aryl or heteroaryl ring heaving 0 to 2 nitrogenatoms and wherein the fused bicyclic heteroaryl ring is attached tocarbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole orthiazole ring; and

b. carbon-8 is not substituted by —OH, —OR¹⁰, —SR¹⁰, or —OR¹¹ when X is—O— and carbon-5 is substituted by aryl or heteroaryl;

further provided that when either T or Z are N, then R^(2c) is absent;or a pharmaceutically acceptable salt thereof.

Among the preferred groups of compounds of Formula (I) of this inventionincluding pharmaceutically acceptable salts thereof are those in thesubgroups below, wherein the other variables of Formula (I) in thesubgroups are as defined above wherein:

a) X is —NH—, —NR⁵— and —O—;

b) T and Z are carbon;

c) T is N and Z is carbon;

d) T is carbon and Z is N;

e) T and Z are carbon, n is 0 and X is —NH—;

f) T is carbon and Z, is N, n is 0 and X is —NH—;

g) T is N and Z is carbon, n is 0 and X is —NH—;

h) T and Z are carbon, n is 0, X is —NH— and R¹ is aryl;

i) T is carbon and Z is N, n is 0, X is —NH— and R¹ is aryl;

j) T is N and Z is carbon, n is 0, X is —NH— and R¹ is aryl;

Among the additionally preferred groups of compounds of Formula (I) ofthis invention including pharmaceutically acceptable salts thereof arethose in the subgroups below, wherein the other valuables of Formula (I)in the subgroups are as defined above wherein:

a) 3-cyanoquinolines, 3-cyano-1,6-naphthyridines and3-cyano-1,7-naphthyridines of Formula (I) wherein:

X is —NH—;

n is 0;

R¹ is a phenyl ring optionally substituted with 1 to 4 substituentswhich may be the same or different independently selected from —H, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵,—R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵,—N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂,—N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q,—OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂N H—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q), —NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)(NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; or apharmaceutically acceptable salt thereof.

b) 3-cyanoquinolines, of Formula (I) wherein:

T and Z are carbon;

X is —NH—;

n is 0;

R¹ is a phenyl ring optionally substituted with 1 to 4 substituentswhich may be the same or different independently selected form —H, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵,—R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵,—N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂,—N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q,—OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q),—NH(C(R⁹)₂)_(q), —NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)_(q)S(O)_(m), —(CR⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰, —C≡C—, cis andtrans —CH∇CH— and cycloalkyl of 3 to 10 carbon atoms;

or a pharmaceutically acceptable salt thereof.

c) 3-cyanoquinolines, 3-cyano-1,6-naphthyridines and3-cyano-1,7-naphthyridines of Formula (I) wherein:

X is —NH—;

n is 0;

A is absent;

R¹ is a phenyl ring optionally substituted with 1 to 4 substituentswhich may be the same or different independently selected from —H, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵,—R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵,—N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂,—N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q,—OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁶,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q), —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q), —NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

or pharmaceutically acceptable salt thereof.

d) 3-cyanoquinolines of Formula (I) wherein:

X is —NH—;

T and Z are carbon;

n is 0;

A is absent;

R¹ is a phenyl ring optionally substituted with 1 to 4 substituentswhich may be the same or different independently selected from —H, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵,—R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵,—N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂,—N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q,—OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵,—R⁶OC(O)Q and YR⁸ groups wherein Y is independently selected from—C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—,—C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q),—NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(CR⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

or pharmaceutically acceptable salt thereof.

e) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

X is —NH—;

n is 0;

R¹ is a phenyl ring substituted with 1 to 4 substituents which may bethe same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂; —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

A is absent;

R⁴ is (C(R⁹)₂)_(r)H;

r is 0;

or a pharmaceutically acceptable salt thereof.

Among the broadly preferred groups of compounds of Formula (I) of thisinvention including pharmaceutically acceptable salts thereof are thosein the subgroups below, wherein the other variables of Formula (I) inthe subgroups are as defined above wherein:

a) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

R^(2a) and R^(2b) are hydrogen;

R^(2c) is selected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH,—OR⁷OR⁵ and —S(O)_(m)R⁵;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which mayhe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NH⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NH⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO_(2—, —SO) ₂NH—, —C(OH)H,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NHR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)—S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—,cis and trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

or a pharmaceutically acceptable salt thereof.

b) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

R^(2a) and R^(2b) are hydrogen;

R^(2c) is selected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH,—OR⁷OR⁵ and —S(O)_(m)R⁵;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(M)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, (C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

A is absent;

or a pharmaceutically acceptable salt thereof.

c) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

R^(2a) and R^(2b) are hydrogen;

R^(2c) is selected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR⁵, —OR⁷OH,—OR⁷OR⁵ and —S(O)_(m)R⁵;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR³, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NH⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NH⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(CR⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R⁴ is —(C(R⁹)₂)_(r)H;

r is 0;

A is absent;

R³ is attached to carbon-7 of Formula (I) and is selected from aryl,heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl wherein each aryl,heteroaryl, bicyclic heteroaryl, alkenyl, and alkynyl is optionallysubstituted by one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)NH₂,G(C(R⁹)₂)_(p)OR¹⁰, G(C(R⁹)₂)_(p)OH, and G(C(R⁹)₂)_(s)R¹²;

or a pharmaceutically acceptable salt thereof.

d) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

R^(2a) and R^(2b) are hydrogen;

R^(2c) is selected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH,—OR⁷OR⁵ and —S(O)_(m)R⁵;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q),—NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R⁴ is —(C(R⁹)₂)_(r)H;

r is 0;

A is absent;

R³ is attached to carbon-6 of Formula (I) and is selected form aryl,heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl wherein each aryl,heteroaryl, bicyclic heteroaryl, alkenyl, and alkynyl is optionallysubstituted by one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)NH₂,G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)OH, and G(C(R⁹)₂)_(p)R¹²;

or a pharmaceutically acceptable salt thereof.

Among the more preferred groups of compounds of Formula (I) of thisinvention including pharmaceutically acceptable salts thereof are thosein the subgroups below wherein the other variables of Formula (I) in thesubgroups are as defined above wherein:

a) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

R^(2a) and R^(2b) are hydrogen;

R^(2c) is attached to carbon-6 or carbon-7 of Formula (I) and isselected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH, —OR⁷OR⁵ and—S(O)_(m)R⁵;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NH⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand —YR⁸ groups wherein Y is independently selected from —C(O)—,—C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q), —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(CR⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R⁴ is —(C(R⁹)₂)_(r)H;

r is 0;

A is absent;

R³ is attached to carbon-6 or carbon-7 of Formula (I) and is selectedfrom aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl whereineach aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl isoptionally substituted by one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,and 1,3-dioxolane;

or a pharmaceutically acceptable salt thereof.

b) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R^(2a) and R^(2b) are H;

R^(2c) is attached to carbon-6 of Formula (I) and is selected from —H,—J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH, —OR⁷OR⁵ and —S(O)_(m)R⁵;

R³ is attached to carbon-7 of Formula (I) and is selected fromheteroaryl, phenyl, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6carbon atoms with each heteroaryl, phenyl, alkenyl and alkynyl groupfurther substituted by one or more of the group —(C(R⁹)₂)_(s)R¹²;

A is absent;

R⁴ is (C(R⁹)₂)_(r)H;

r is 0;

or a pharmaceutically acceptable salt thereof.

c) 3-cyanoquinolines of Formula (I) wherein:

T and Z are carbon;

X is —NH—;

n is 0;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NH—R⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand —YR⁸ groups wherein Y is independently selected from —C(O)—,—C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(CR⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹—, —C≡C—, cisand trans —CH═CH— cycloalkyl of 3 to 10 carbon atoms;

R^(2a) and R^(2b) are H;

R^(2c) is attached to carbon-7 of Formula (I) and is selected from —H,—J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH, —OR⁷OR⁵ and —S(O)_(m)R⁵;

R³ is attached to carbon-6 of Formula (I) and is selected fromheteroaryl, phenyl, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6carbon atoms with each heteroaryl, phenyl, alkenyl and alkynyl groupsubstituted by one or more of the group —(C(R⁹)₂)_(s)R¹²;

A is absent;

R⁴ is —(C(R⁹)₂)_(r)H;

r is 0;

or a pharmaceutically acceptable salt thereof.

d) 3-cyanoquinolines of Formula (I) wherein:

X is —NH—;

T and Z are carbon;

n is 0;

R^(2a) and R^(2b) are H;

R^(2c) attached to carbon-6- or carbon-7 of Formula (I) and is selectedfrom —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH, —OR⁷OR⁵ and—S(O)_(m)R⁵;

R¹ is phenyl optionally substituted which 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁷)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand —YR⁸ groups wherein Y is independently selected form —C(O)—,—C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰, —C≡C—, cis-and trans- —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R³ is attached to carbon-6 or carbon-7 of Formula (I) and is alkenyl of2 carbon atoms;

A is absent;

or a pharmaceutically acceptable salt thereof.

e) 3-cyanoquinolines of Formula (I) wherein:

X is —NH—;

T and Z are carbon;

n is 0;

R^(2a) and R^(2b) are H;

R^(2c) is attached to carbon-6 or carbon-7 of Formula (I) and isselected from —H, —J, —CF₃, —OCF₃, —R⁵, —OR⁵, —OR¹¹, —OR⁷OH, —OR⁷OR⁵ and—S(O)_(m)R⁵;

R¹ is phenyl optionally substituted with 1 to 4 substituents which maybe the same or different independently selected from —H, —J, —NO₂, —NH₂,—OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵,—OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵,—R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵, —R⁶OC(O)Qand YR⁸ groups wherein Y is independently selected from —C(O)—, —C(O)O—,—OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—, —SO₂NH—, —C(OH)H—,—O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—, —NH(C(R⁹)₂)_(q)—,—NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms;

R³ is attached to carbon-6 or carbon-7 of Formula (I) and is alkynyl of2 carbon atoms;

A is absent;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention or a pharmaceutically acceptablesalt thereof are:

4-(4-Chloro-2-fluoroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(2-pyridinyl)ethenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile,

7-[5-(4-Morpholinylmethyl)-3-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,

4-(4-Benzylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-{5-[2-(4-morpholinyl)ethyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[(E/Z)-5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[3-(dimethylamino)-1-propynyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[(E/Z)-6-(4-morpholinyl)-1-hexenyl]-3-quinolinecarbonitrile,

7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[5-(2-pyridinyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(E)-3-(4-morpholinyl)-1-propenyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[4-(4-morpholinyl)butyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{3-[2-(4-morpholinyl)ethyl]phenyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-methoxy-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-ethyl-1-piperazinyl)ethyl]phenyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{3-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinylmethyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloroanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

(2R)-1-({5-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-furyl}methyl)-2-pyrrolidinecarboxamide,

7-[5-(4-Morpholinylmethyl)-3-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-methoxyphenyl)ethenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

7-[5-(4-Morpholinylmethyl)-2-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(phenylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-(1H-pyrrol-1-yl)-3-quinolinecarbonitrile,

4-(3-Bromoanilino)-6-(2-formyl-1H-pyrrol-1-yl)-3-quinolinecarbonitrile,

4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-(1H-pyrrol-1-yl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{1-[2-(4-morpholinyl)ethyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-(4-morpholinylmethyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(1-methyl-5-[(4-methyl-1-piperazinyl)methyl]-1H-pyrrol-2-yl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(phenylsufonyl)ethyl]amino}methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(methylsulfonyl)ethyl]amino}-methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

7-(5-{[Bis(2-hydroxyethyl)amino]methyl}-2-furyl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-furyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{2-Chloro-4-fluoro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{2-Chloro-5-methoxy-4-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[6-4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,

7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile,

(2R)-1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-pyrrolidinecarboxamide,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(phenylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(diethylamino)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(methylsufonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-methoxyphenyl)ethynyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(2-pyridinyl)ethynyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-pyrrol-1-yl-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{(2-[(dimethylamino)methyl]-1H-pyrrol-1-yl}-3-quinolinecarbonitrile,

7-[5-(1,3-Dioxolan-2-yl)-3-thienyl]-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile,

4-[3-Methyl-4-(2-pyridinylmethoxy)anilino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyanilino]-7-(2-formyl-1-methyl-1H-imidazol-5-yl)quinoline-3-carbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(1-piperazinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-isopropyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

(E)-3-[3-Cyano-4-(2,4-dichloro-1-methoxyanilino)-7-quinolinyl]-2-propenoicacid,

(1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)aceticacid,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(hydroxymethyl)phenyl]-3-quinolinecarbonitrile,

7-[4-(Chloromethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(1H-1,2,3-triazol-1-methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(1H-pyrrol-2-yl)-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyanilino]-7-[4-(1H-tetraazol-5-yl)phenyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

Methyl1-{[6-(4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3-pyridinyl]methyl}-4-piperidinecarboxylate,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-thiomorpholinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(morpholin-4-ylmethyl)-pyridin-2-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxylanilino)-7-(3-formyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(2-formylphenyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(1-naphthyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(2-naphthyl)-3-quinolinecarbonitrile,

N-{3-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]phenyl}acetamide,

7-(1-Benzofuran-2-yl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

7-(1-Benzothien-2-yl)-4-2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzoic acid,

4-(2,4-Dichloro-5-methoxyanilino)-7-(3-nitrophenyl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

7-[3,4-Bis(4-morpholinylmethyl)phenyl-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-y)sulfanyl]anilino}-6-methoxy-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-(4-methoxyphenyl)-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(4-morpholinylcarbonyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(2-methoxy)ethoxyl]phenyl}-3-quinolinecarbonitrile,

4-(2-Chloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[4-(Benzyloxy)-3-chloroanilino]-7-[3,4-bis(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(2-chloro-5-methoxy-4-methylanilino)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

tert-Butyl4-{4-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-3-cyano-7-quinolinyl]benzyl}-1-piperazinecarboxylate,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-morpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-phenylethenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(2-phenylethynyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-methylphenyl)ethynyl]-3-quinolinecarbonitrile,

tert-Butyl(E)-3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-propenoate,

4-(2,4-Dichloro-5-methoxyanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrile,

Ethyl(1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)acetate,

Ethyl1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-piperidinecarboxylate,

4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinyl)-1-propynyl]-3-quinolinecarbonitrile,

1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-piperidinecarboxylicacid,

Ethyl1-(4-{3-cyano-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-quinolinyl}benzyl)-3-piperidinecarboxylate,

1-(4-{3-Cyano-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-quinolinyl}benzyl)-3-piperidinecarboxylicacid,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{4-[(1-oxido-4-thiomorpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,

7-(3-Chloro-1-propynyl)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-thiomorpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-2-furyl-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(hydroxymethyl)-1-methyl-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(3-formyl-2-thienyl)-3-quinolinecarbonitrile,

tert-Butyl2-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-1H-pyrrole-1-carboxylate,

7-[1,1′-Biphenyl]-4-yl-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinyl)-1-propynyl]-3-quinolinecarbonitrile,

4-(4-Chloro-5-methoxy-2-methylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,

7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-formyl-2-pyridinyl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

7-(3-Aminophenyl)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile,

1-{[6-{4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3-pyridinyl)methyl]-2-pyridinyl}-4-piperidinecarboxylicacid,

1-{6-[3-Cyano-4-(2,4-dichloro-5-methoxyphenylamino)-quinolin-7-yl]-pyridin-3-ylmethyl}-piperidine-4-carboxylicacid methyl ester,

1-{6-[3-Cyano-4-(2,4-dichloro-5-methoxyphenylamino)-quinolin-7-yl]-pyridin-3-ylmethyl}-piperidine-4-carboxylicacid,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-chloro-2-pyridinyl)-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[5-(1-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[6-(4-morpholinyl)-3-pyridinyl-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-morpholinyl)-3-pyridinyl-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinyl)-5-pyrimidinyl]-3-quinolinecarbonitrile,

4-{(3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-morpholinyl]-3-pyridinyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[2-(4-morpholinyl]-5-pyrimidinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{6-[4-(4-morpholinylmethyl)phenoxy]-3-pyridinyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(4-methoxyphenyl)-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{6-[(4-ethyl-1-piperazinyl)methyl]2-pyridinyl}-3-quinolinecarbonitrile,

4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{6-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-((3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-4-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{3-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[4-(1-pyrrolidinyl)-1-piperidinyl]-3-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(2-methoxyethyl)(methyl)amino]3-pyridinyl}-3-quinolinecarbonitrile,

Ethyl1-{5-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-3-cyano-7-quinolinyl]-2-pyridinyl}-4-piperidinecarboxylate,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[4-(2-hydroxyethyl)-1-piperazinyl]-3-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(2-hydroxyethyl)(methyl)amino]-3-pyridinyl}-3-quinolinecarbonitrile,

4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]-methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-thiomorpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-ethyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-methyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(6-formyl-3-pyridinyl)-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl)-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,

4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-isopropyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-2-(4-morpholinylmethyl)-1H-imidazol-5-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-{1-methyl-2-[(4-methyl-1-piperazinyl)methyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(2-formyl-1-methyl-1H-imidazol-5-yl)-6-methoxy-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(2-pyridinyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

Methyl1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinecarboxylate,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[1-methyl-2-(4-morpholinylmethyl)-1H-imidazol-5-yl]-3-quinolinecarbonitrile,

4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{1-methyl-2-[(4-methyl-1-piperazinyl)methyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,

4-(2-Chloro-5-methoxy-4-methylanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-[(4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2-Chloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinecarboxylicacid,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

Additionally, preferred compounds of the invention or a pharmaceuticallyacceptable salt thereof are:

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-y)sulfanyl]anilino})-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[2-dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(1-piperidinylmethyl)phenyl]3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl-2-furyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl)-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-{[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-{[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl-3-quinolinecarbonitrile,

4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-({3-chloro-4′-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl)amino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4′-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1′-biphenyl]-4-yl]amino}-7-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-5-methyl-4′-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[(1,1′-biphenyl]-4-yl)amino]-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-4′-(4-morpholinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4′-([(2-hydroxyethyl)amino]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-({3-chloro-5-methyl-4′-[(4-methyl-1-piperazinyl)methyl][1,1′-biphenyl]-4-yl)amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-4′-({[3-(4-morpholinyl)propyl]amino}methyl)[1,1′-biphenyl]-4-yl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-4′-(1-piperidinylmethyl)[1,1′-biphenyl)-4-yl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-({3-chloro-4′-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl}amino]-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4′-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-({(3-chloro-3′-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl}amino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-3′-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1′-biphenyl]-4-yl]amino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-5-methyl-3′-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[1,1′-biphenyl]-4-yl)amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-[(3-chloro-5-methyl-3′-{[(4-pyridinylmethyl)amino]methyl}[1,1′-biphenyl]-4-yl)amino]-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-3′-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-5-methyl[1,1′biphenyl]-4-yl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-3′-(4-morpholinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-3′-{[(2-hydroxyethyl)amino]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-({3-chloro-5-methyl-3′-[(4-methyl-1-piperazinyl)methyl][1,1′-biphenyl]-4-yl}amino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-3′-({[3-(4-morpholinyl)propyl]amino}methyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-5-methyl-3′-(1-piperidinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-({3-chloro-3′-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl}amino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[(3-chloro-3′-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2-chloro-4-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-6-methylanilino}-7-[5-({[2-(dimethylanilino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[2-chloro-6-methyl-4-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)anilino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[2-chloro-6-methyl-4-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)anilino]7-(5-{[(4-piperidinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{2-chloro-4-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-6-methylanilino-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2-chloro-6-methyl-4-[5-(4-morpholinylmethyl)-3-thienyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2-chloro-6-methyl-4-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}anilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{2-chloro-6-methyl-4-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{2-chloro-6-methyl-4-[5-(1-piperidinylmethyl)-3-thienyl]anilino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2-chloro-4-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-6-methylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-[2-chloro-4-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-6-methylanilino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-5[-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-[(3-chloro-4-phenoxyphenyl)annoy]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylfanyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-[3-chloro-4-(phenylsulfanyl)phenyl]amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]methyl}-2-furyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-furyl]3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,

4-[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl-3-thienyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,

7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,

7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,

4-[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino)-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,

7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,

4-[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-51-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-pyridinyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,

4-(2,4-dichloro-5-methoxyanilino)-7-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl]-3-quinolinecarbonitrile,

7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[4-(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[4-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[3(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[3-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-((3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[5-(4-morpholinylmethyl)-3-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-(5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,

7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,and

7-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl)-2-pyridinyl]-4-(3,4,5trimethoxyanilino)-3-quinolinecarbonitrile,

For the compounds of Formula (I) defined above and referred to herein,unless otherwise noted, the following terms are defined:

Halogen, as used herein means chloro, fluoro, bromo and iodo.

Alkyl as used herein means a branched or straight chain having from 1 to12 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplaryalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobultyl,t-butyl, pentyl and hexyl optionally substituted with phenyl, phenyloptionally substituted with one or more substituents preferably from oneto three substituents independently selected from alkyl, alkoxy,perhaloalkyl, halogen, nitro, hydroxy, amino, carboxy, carboxyalkyl,alkylamino and dialklylamino, thioalkyl, alkoxycarbonyl and acyl.

Alkenyl as used herein means a branched or straight chain having from 2to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, thechain containing at least one carbon-carbon double bond and all possibleconfigurational isomers. Alkenyl, may be used synonymously with the termolefin and includes alkylidenes. Exemplary alkenyl groups includeethenyl, propenyl, 1,4-butadienyl, 3-hexen-1-yl and the like optionallysubstituted with phenyl, phenyl optionally substituted with one or moresubstituents preferably from one to three substituents independentlyselected from alkyl, alkoxy, perhaloalkyl, halogen, nitro, hydroxy,amino, carboxy, carboxyalkyl, alkylamino and dialkylamino, thioalkyl,alkoxycarbonyl and acyl.

An alkynyl group is defined as straight or branched carbon chain of 2 to6 carbon atoms that contains at least one carbon-carbon triple bond andincludes propynyl and the like optionally substituted with phenyl,phenyl optionally substituted with one or more substituents preferablyfrom one to three substituents independently selected from alkyl,alkoxy, perhaloalkyl, halogen, nitro, hydroxy, amino, carboxy,carboxyalkyl, alkylamino and dialkylamino, thioalkyl, alkoxycarbonyl andacyl.

Alkoxy as used herein means an alkyl-O— group in which the alkyl groupis as previously described. Exemplary alkoxy groups include methoxy,methoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy and polyethersincluding —O—(CH₂)₂OCH₃.

Cycloalkyl as used herein means a simple carbocycle having a saturatedring having from 3 to 10 carbon atoms and more preferably from 3 to 6carbon atoms optionally substituted with 1 to 3 independently selectedalkyl groups of 1 to 12 carbon atoms. Exemplary cycloalkyl rings includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl and thelike.

Aryl is used herein means a mono or bicyclic aromatic ring having from 6to 12 carbon atoms. Monocyclic rings preferably have 6 members andbicyclic rings preferably have 8, 9, 10 or 12 membered ring structures.Exemplary aryl groups include phenyl, alpha-naphithyl, beta-naphthyl,indene, and the like independently substituted with one or moresubstituents and more preferably with 1 to 4 substituents.

Heteroaryl denotes an unsubstituted or optionally substituted monocyclic5 or 6 membered ring, which contains 1 to 4, or particularly 1 or 2heteroatoms which may be the same or different. Nitrogen, oxygen andsulfur are the preferred heteroatoms, provided that the heteroaryl doesnot contain O—O, S—S or S—O bonds. Specific examples include thiophene,furan, pyrrol, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, thiazole, oxazole, isothiazole, isoxazole, 1,3,4-oxadiazole,1,2,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine, pyrazine,pyridazine and 1,3,5-triazine. The heteroaryl ring may be oxidized whena heteroatom is a nitrogen atom to provide the corresponding N-oxide,including pyridine-N-oxide. The heteroaryl ring may be oxidized on asulfur atom to provide the corresponding sulfoxide or sulfone, includingthiophene-1-oxide. The heterocyclic ring may contain a carbonyl group onone of the carbon atoms, such as 1,3,4-oxadiazol-2-one.

Bicyclic heteroaryl as used herein refers to saturated or partiallyunsaturated bicyclic fused rings having 8 to 20 ring atoms containing 1to 4 heteroatoms which may be the same or different independentlyselected from nitrogen, oxygen and sulfur optionally substituted with 1to 3 independently selected substituents which may be the same ordifferent provided that the bicyclic heteroaryl does not contain O—O,S—S or S—O bonds. Specific examples include: indole, 2,3-dihydroindole,2-indazole, isoindazole, quinoline, isoquinoline, tetrahydroquinoline,benzofuran, benzothiophene, benzimidazole, benzotriazole, benzothiazole,benzoxazole, benzisoxazole, 1,2-benzopyran, cinnoline, phthalazine,quinazoline, 1,8-naphthyridine, pyrido[3,2-b]pyridine,pyrido[3,4-b]pyridine, pyrido[4,3-b]pyridine, pyrido[2,3-d]pyrimidine,purine, and ptenidine and the like. Either or both rings of the bicyclicring system may be partially saturated, or fully saturated. The bicyclicgroup may be oxidized on a nitrogen atom to provide the correspondingN-oxide, such as quinoline-N-oxide. The bicyclic group may be oxidizedon a sulfur atom to provide the corresponding sulfoxide or sulfone, suchas benzothiophene-1-oxide. The bicyclic ring system may contain acarbonyl group on one of the carbon atoms, such as 2-indanone.

Heterocyclyl means a saturated or partially unsaturated monocyclicradical containing preferably 3 to 8 ring atoms, more preferably 3 to 7ring atoms and most preferably 5 to 6 ring atoms selected from carbon,nitrogen, oxygen and sulfur with at least 1 and preferably 1 to 4, morepreferably 1 to 2 nitrogen, oxygen or sulfur as ring atoms. Specificexamples include but are not limited to morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperidine,piperazine, pyrrolidine, aziridine, oxirane, tetrahydrothiophene,tetrahydrofuran, 1,2-pyran, 1,4-pyran, dioxane, 1,3-dioxolane andtetralhydropyran. The heterocyclyl ring may be oxidized on atri-substituted nitrogen atom to provide the corresponding N-oxide, suchas N-ethylpiperazine-N-oxide, or the heterocyclyl ring may contain acarbonyl group on one of the carbon atoms, such as pyrrolidinone.

Thioalkyl as used herein means an alkyl-S— group in which the alkylgroup is as previously described. Thioalkyl groups include thiomethyland the like.

A carboxy group is defined as —C(O)OH, and an alkoxycarbonyl group isdefined as —C(O)OR where R is alkyl of 1 to 6 carbon atoms and includesmethoxycarbonyl, allyloxycarbonyl and the like.

Carboxyalkyl is defined as HOOC-alkyl of 1 to 12 carbon atoms.

Alkylamino is defined as a nitrogen atom substituted with an alkyl of 1to 12 carbon atoms.

Dialkylamino is defined as a nitrogen atom disubstituted with an alkylof 1 to 12 carbon atoms.

An acyl group is defined as a group —C(O)R where R is an alkyl or arylradical and includes acetyl, trifluoroacetyl, benzoyl and the like.

Phenyl as used herein refers to a 6-membered aromatic ring.

Where terms are used in combination, the definition for each individualpart of the combination applies unless defined otherwise. For instance,perhaloalkyl refers to an alkyl group, as defined above and perhalorefers to all hydrogen atoms on the alkyl group being substituted with ahalogen as define above. An example is trifluoromethyl.

Some of the compounds of the invention have centers of asymmetry. Thecompounds may, therefore, exist in at least two and often morestereoisomeric forms. The present invention encompasses allstereoisomers of the compounds whether free from other stereoisomers oradmixed with other stereoisomers in any proportion and thus includes,for instance, racemic mixture of enantiomers as well as thediasteieomeric mixture of isomers. The absolute configuration of anycompound may be determined by conventional X-ray crystallography.Optically active isomers may be prepared, for example, by resolvingracemic derivatives or by asymmetric synthesis. The resolution can becarried out by the methods known to those skilled in the art such as inthe presence of a resolving agent, by chromatography, or combinationsthereof.

The compounds of Formula (I) may be obtained as inorganic or organicsalts using methods known to those skilled in the art (Richard C.Larock, Comprehensive Organic Transformations, VCH publishers 411-415,1989). It is well known to one skilled in the art that an appropriatesalt form is chosen based on physical and chemical stability,flowability, hydroscopicity and solubility.

Pharmaceutically acceptable salts of the compounds of Formula (I) withan acidic moiety may be formed from organic and inorganic bases. Forexample with alkali metals or alkaline earth metals such as sodium,potassium, lithium, calcium, or magnesium or organic bases andN-tetraalkylammonium salts such as N-tetrabutylammonium salts.Similarly, when a compound of this invention contains a basic moiety,salts may be formed from organic and inorganic acids. For example saltsmay be formed from acetic, propionic, lactic, citic, tartaric, succinic,fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric,hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic,naphthialenesulfonic, benzenesulfonlic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids. The compounds canalso be used in the form of esters, carbamates and other conventionalprodrug forms, which when administered in such form, convert to theactive moiety in vivo.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention in combination orassociation with a pharmaceutically acceptable carrier. In particular,the present invention provides a pharmaceutical composition whichcomprises an effective amount of a compound of this invention and apharmaceutically acceptable carrier.

The compounds of this invention are certain substituted3-cyanoquinolines, 3-cyano-1,6-naphthyridine and3-cyano-1,7-naphthyridine containing compounds.

The quinoline, 1,6-nphthyridine and 1,7-naphthyridine ring systems willbe numbered as indicated in the formulae:

In addition to the utilities, described herein some of the compounds ofthis invention are intermediates useful for the preparation of othercompounds of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds of this invention may be prepared from: (a) commerciallyavailable starting materials (b) known starting materials which may beprepared as described in literature procedures or (c) new intermediatesdescribed in the schemes and experimental procedures herein.

Reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformation being effected.It is understood by those skilled in the art of organic synthesis thatthe various functionalities present on the molecule must be consistentwith the chemical transformations proposed. This may necessitatejudgement as to the order of synthetic steps. Appropriate considerationmust be made as to the protection of reactive functional groups toprevent undesired side reactions. For example, it may be necessary toprotect primary or secondary amino or hydroxyl groups. Suitableprotecting groups include, but are not limited to, tert-butoxycarbonyl(BOC), trimethylsilylethanesulfonamide (SES), benzyloxycarbonyl (CBZ)and benzyl (Bn) protecting groups. The BOC protecting group may beremoved by treatment with in acid such as trifluoroacetic acid orconcentrated hydrochloric acid and the SES protecting group may beremoved with a fluoride salt, such as cesium fluoride ortetrabutylammonium fluoride. The CBZ and Bn protection groups may beremoved by catalytic hydrogenation. Additional suitable protectinggroups for hydroxy substituents include, but are not limited to,t-butyldimethylsilyl (TBDMS), tetrahydropyranyl (THP), or isopropyl(i-Pr) protecting groups. The TBDMS and THP protecting groups may beremoved by treatment with an acid such as acetic acid or hydrochloricacid while the i-Pr protecting group may be removed by aluminumtrichloride.

Substituents on the starting materials may be incompatible with some ofthe reaction conditions. Such restrictions to the substituents which arecompatible with the reaction conditions will be apparent to one skilledin the salt. Reactions were run under inert atmospheres whereappropriate.

The preparation of the compounds and intermediates of this inventionencompassed by Formula (I) is described as follows where keyintermediates for the preparation of compounds of Formula (I) arecompounds of Formulae (II), (III), and (IV) wherein LG is attached to acarbon atom and designates a leaving group preferably Br, I or OTf whereOTf designates a trifluoromethanesulfonate (triflate) group.

As shown in Scheme 1, a 3-bromoaniline 1 where T and Z are carbon atomsand R^(2a), R^(2b) and R^(2c) are hereinbefore defined and LG is bromoand ethyl(ethoxymethylene)cyano acetate 2 may be heated at temperaturesranging from 60 to 120° C. either neat or in an inert solvent whichincludes toluene and the like followed by cyclization in a 3:1 mixtureof diphenyl ether and biphenyl at an optimal temperature of 260° C. toprovide a mixture of isomers7-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 3a and5-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 3b. The isomers may beseparated by either recrystallization or chromatography. Heating of7-bromo-4-oxo-1,4-dihydroquinoline-3-cabonitrile 3a with a chlorinatingreagent selected from phosphorus oxychloride and oxalyl chloride eitherneat or in an inert solvent which includes methylene chloride, providesthe corresponding 7-bromo-4-chloro-3-cyanoquinoline 4 where T and Z arecarbon atoms and R^(2a), R^(2b) and R^(2c) are hereinbefore defined andLG is bromo. Reaction of 7-bromo-4-chloro-3-cyanoquinoline 4 with ananiline, phenol, thiophenol, amine, alcohol or thiol reagent 5 havingthe formula HX—(CH₂)_(n)—R¹, wherein R¹, X and n are hereinbeforedefined, gives the 3-cyanoquinolines of Formula (II) where the leavinggroup LG may be bromo, where T and Z are carbon atoms, X, R¹, R^(2a),R^(2b) and R^(2c) are hereinbefore defined. The condensation may beaccelerated by heating the reaction mixture together with a catalyticamount or one equivalent of pyridime hydrochloride or by using organicbases selected from triethylamine, 4-dimethylaminopyridine, anddiazabicyclo[5.4.0]undec-7-ene and the like or sodium hydride in aninert solvent, which includes tetrahydrofuan and the like or sodium orpotassium alkoxides in the absence of solvent or in an inert solvent.

The reaction sequence shown in Scheme 1 may be modified by substitutionof 3-iodoaniline for 3-bromoaniline 1, where the LG may be iodo in placeof bromo with the resulting compounds of Formula (II) now containing a7-iodo group.

Scheme 2 shows an alternate route for the preparation of compounds ofFormula (II). Reaction of 5-bromoanthranilic acid or ester 6 where T andZ are carbon atoms and R^(2a), R^(2b) and R^(c) are hereinbefore definedwith N,N′-dimethylformamide dimethyl acetal (DMF-DMA), in the presenceor absence of a co-solvent selected from dimethylformamide and toluenegives the corresponding intermediate amidine which may be furtherreacted with the lithium anion of acetonitrile prepared by using a basewhich includes n-butyllithium, lithium di-isopropylamine, or the like inan inert solvent, preferably tetrahydrofuran, to give6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 7. Heating6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 7 with a chlorinatingreagent selected from phosphorus oxychloride and oxalyl chloride eitherneat or in a solvent such as methylene chloride, provides thecorresponding 6-bromo-4-chloro-3-cyanoquinoline 8 where T and Z arecarbon atoms and R^(2a), R^(2b) and R^(2c) are hereinbefore defined,which when reacted with an aniline, phenol, thiophenol, amine, alcoholor thiol reagent 5 of the formula HX—(CH₂)_(n)—R¹, wherein R¹, X and nare as previously defined, gives the 3-cyanoquinolines of Formula (II)where the leaving group LG may be bromo.

Alternatively compounds of Formulae (II), (III) or (IV) containing atriflate (-OTf) leaving group may be prepared as shown in Scheme 3. Thephenolic group of an ester of formula 9 where T and Z are carbon atomsand R^(2a), R^(2b) and R^(2c) are hereinbefore defined is protected witha benzyl group and subsequent nitration provides the 2-nitro derivative10. Removal of the benzyl group, formation of the triflate and reductionof the nitro group provides the aniline 11 where T and Z are carbonatoms and R^(2a), R^(2b) and R^(2c) are hereinbefore declined. Furtherreaction of aniline 11 with N,N′-dimethylformamide dimethyl acetal(DMF-DMA), in the presence or absence of a co-solvent selected fromtoluene and N,N-dimethylformamide, gives the corresponding intermediateamidine which is further reacted with the lithium anion of acetonitrileprepared by using a base which includes n-butyllithium, lithiumdi-isopropylamine, or the like in an inert solvent, preferablytetrahydrofuran, to give quinoline-3-carbonitrile 12. Heatingquinoline-3-carbonitrile 12 with a chlorinating reagent selected fromphosphorus oxychloride and oxalyl chloride either neat or in it solventsuch as methylene chloride, provides the corresponding4-chloro-3-cyanoquinoline 13 where T and Z are carbon atoms and R^(2a),R^(2b) and R^(2c) are hereinbefore defined, which when reacted with ananiline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of theformula HX—(CH₂)_(n)—R¹, wherein R¹, X and n are as previously defined,gives the 3-cyanoquinolines of Formula (II) where the leaving group LGis -OTf where T and Z are carbon atoms and R^(2a), R^(2b) and R^(2c) arehereinbefore defined.

The compounds of Formulae (III) and (IV) may be prepared by routesanalogous to those shown in Schemes 1-3. As shown in Scheme 4 oxidationof a 2-bromopyridine 14, where T is a nitrogen atom, Z is a carbon atom,R^(2a), R^(2b) are hereinbefore defined and R^(2c) is absent and LG isbromo, using m-chloroperbenzoic acid forms the N-oxide followed bynitration to afford a 2-bromo-4-nitro-pyridine-N-oxide which followingsubsequent reduction using iron in the presence of ammonium chlorideprovides a 4-amino-2-bromopyridine 16. Using conditions analogous tothose in Scheme 1, a 4-amino-2-bromopyridine 16 andethyl(ethoxymethylene)cyano acetate 2 are heated at temperatures rangingfrom 60 to 120° C. either neat or in an inert solvent which includestoluene and the like followed by cyclization in a 3:1 mixture ofdiphenyl ether and biphenyl at an optimal temperature of 260° C. toprovide a 7-bromo-4-oxo-1,4,-dihydro-1,6-naphthyridine-3-carbonitrile 17where T is a nitrogen atom, Z is a carbon atom, R^(2a) and R^(2b) arehereinbefore defined. Heating of a7-bromo-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carbonitrile 17 with achlorinating agent selected from phosphorus oxychloride and oxalylchloride either neat or in a solvent such as methylene chloride,provides the corresponding7-bromo-4-chloro-1,6-naphthyridine-3-carbonitrile 18. Reaction of a7-bromo-4-chloro-1,6-naphthyridine-3-carbonitrile 18 with an aniline,phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formulaHX—(CH₂)_(n)—R¹, wherein R¹, X and n are as previously defined, givesthe 3-cyano-1,6-naphthyridines of Formula (III) where the leaving groupLG is bromo and where T is a nitrogen atom, Z is a carbon atom, R^(2a),R^(2b), X, R¹ and n are hereinbefore defined.

Compounds of Formulae (II), (III) and (IV) may be converted to compoundsof Formula (I) of the invention by replacement of the leaving group (LG)of Formulae (II), (III) and (IV) with organometallic reagents andformation of a carbon-carbon bond. The organometallic reagents, whichare organoboron and organotin reagents may be prepared as shown inScheme 5.

Organoboron reagents of formula R⁴—A—R³—BL¹L² 19, wherein R³ is aryl,heteroaryl, and bicyclic heteroaryl, L¹ and L² are suitable ligandsindependently selected from alkoxy, alkyl and hydroxy and readilyobtained by standard procedures, (R. D. Larsenl, Current Opinoion DrugDiscovery and Development, 2, No. 6, 651-667(1999). Compounds of formulaR⁴—A—R³—H 20 or R⁴—A—R³—Br 21 may be converted to the corresponding inorganolithium by treatment with a lithium base which include n-BuLi. Theorganolithium may then be treated with an organoboron reagent of formulaQ¹—BL¹L² 22 where Q¹ is defined as a leaving group selected from alkoxyand the like to provide compounds of formula R⁴—A—R³—BL¹L² 19.Organoboron reagents of formula Q¹—BL¹L² 9 include alkyl boratesincluding tri-isopropyl borate, wherein one of the tri-isopropyl groupsfunctions as the leaving group Q¹. Suitable L¹ and L² groups areindependently hydroxy, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to12 carbon atoms. In addition, the ligands L¹L² may be taken togetherwith the boron to which they are attached to form a cyclic boron ester,where L¹L² may be oxyethyleneoxy and the like. Alternatively a compoundof formula R⁴—A—R³—Br 21 may be treated with an organoboron compoundsuch as bis(pinacolato)diboron and the like in the presence of potassiumacetate and a palladium catalyst including[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane in a solvent selected from dimethyl sulfoxide,N,N-dimethylformamide (DMF), and dioxane and the like to provide theorganoboron compound of formula R⁴—A—R³—BL¹L² 19.

Organotin reagents of formula R⁴—A—R³—SnR₃ 24 may be readily obtained bystandard procedures. Compounds of formula R⁴—A—R³—H 20 or R⁴—A—R³—Br 21may be converted to the corresponding organolithium compound bytreatment with a lithium base which includes n-BuLi. The organolithiumcompound may then be treated with an organotin compound of formulaQ¹—SnR₃ 23 which include tri-n-butylstannyl chloride where Q¹ is achloro leaving group to afford organotin reagents of formulaR⁴—A—R³—SnR₃ 24. Organoboron reagents of formula 19 and organotinreagant of formula 24 may be generated in situ and used withoutpurification.

Scheme 6 shows a route for the preparation of compounds of Formula (I)from the reaction of compounds of Formulae (II), (III) and (IV) in asolvent selected from tetrahydrofuran, dioxane, and ethylene glycoldimethyl ether and the like at temperatures preferably 60 to 150° C.with reagents R⁴—A—R³—BL¹L² 19 or R⁴—A—R³—SnR₃ 24 in the presence ofcatalysts which include tetrakis(triphenylphosphine)palladium(0),palladium(II)chloride, nickel(II)bromide and the like, where A, R³ andR⁴ are hereinbefore defined.

Specifically as shown in Scheme 7 compounds of Formula (I) wherein R³ isan alkene may be prepared via reaction of compounds of formulaR⁴—A—CH═CH₂ 25 with compounds of Formula (II), (III) or (IV) in thepresence of triphenylphosphine and a palladium catalyst, which includepalladium acetate. Preferred solvents include trialkylamines such astriethylamine, or alternatively N,N-dimethylformamide with an equivalentof a base which include sodium bicarbonate. Similarly, compounds ofFormula (I) wherein R³ is an alkyne group may be obtained by reaction ofcompounds of formula R⁴—A—C≡CH 26 with compounds of Formula (II), (III)or (IV) in the presence of triphenylphosphine, copper(I)iodide and apalladium catalyst, which include dichlorobis(triphenylphosphine)palladium(I).

As shown in Scheme 8, an alternate route to some compounds of Formula(I) involves reaction of compounds of Formulae (II), (III) and (IV) witha stannane reagent 27 where R³ is an aryl, heteroaryl, or bicyclicheteroaryl which include 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)furan,2-(1,3-dioxolan-2-yl)-1-methyl-5-(tributylatannyl)imidazole. Thestannane reagent 27 may be reacted with compounds of Formulae (II),(III) and (IV) in an inert solvent which includes tetrahydrofuran ordioxane and the like in the presence of a palladium catalyst such asbis(triphenylphosphine)palladium(II)chloride or1,4-bis(diphenylphosphino)butane palladium(II)chloride to afford anacetal 29. The acetal protecting group may be removed by acidhydrolysis, preferably using aqueous hydrochloric acid with a cosolventsuch as tetrahydrofuran, to give the aldehyde 29. Alternatively thealdehyde 29 may be obtained directly by reaction of compounds ofFormulae (II), (III) and (IV) with a boronic acid reagent 30 where R³ isaryl, heteroaryl and bicyclic heteroaryl which include 4-formylphenylboronic acid and the like, to also give aldehyde 29. The boronic acidreagent 30 may be reacted with compounds of Formulae (II), (III) and(IV) in a solvent selected from tetrahydrofuran and dioxane in thepresence of a palladium catalyst which includesbis(triphenylphosphine)palladium(II)chloride or1,4-bis(diphenylphosphino)butane palladium(II)chloride. Aldehyde 29 maybe treated with an amine 31 of formula HNR¹³R¹⁴, in a solvent selectedfrom methylene chloride, dioxane and tetrahydrofuan, in the presence ofa reducing agent such as sodium triacetoxyborohydride or sodiumcyanoborohydride with the optional addition of a catalyst which includesacetic acid and the like.

Alternatively compounds of the invention may be prepared by the routesshown in Schemes 9 and 10 where the olganotin reagent R⁴—A—R³—SnR₃ 24 ororganoboron reagent R⁴—A—R³—BL¹L² 19, may be coupled to cyano compound32 where T, Z, R^(2a), R^(2b) and R^(2c) are hereinbefore defined togive intermediate 33 which may then be converted to the 4-chlorointermediate 34 by reaction with a chlorinating reagent selected fromphosphorous oxychloride, oxalyl chloride and polymer supportedtriphenylphosphine and carbon tetrachloride, which when reacted with ananiline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of theformula HX—(CH₂)_(n)—R¹, wherein R¹, X and n are as previously defined,gives compounds of Formula, (I) of the invention

Referring to Scheme 10, compounds of the formula R⁴—A—CH═CH₂ 25 coupledto cyano compound 32 where T, Z, R^(2a), R ^(2b) and R^(2c) arehereinbefore defined give intermediate 35 which may then be converted tothe 4-chloro intermediate 36 by reaction with a chlorinating reagentselected from phosphorous oxychloride, oxalyl chloride and polymersupported triphenylphosphine and carbon tetrachloride, which whenreacted with an aniline, phenol, thiophenol, amine, alcohol or thiolreagent 5 of the formula HX—(CH₂)_(n)—R¹, wherein R¹, X and n are aspreviously defined, to give compounds of Formula (I).

Additional key intermediates for the preparation of compounds of Formula(I) are compounds of Formulae (V), (VI), and (VII), when in the primaryamino group is attached to a carbon atom.

Compounds of Formula (V) where T and Z are carbon atoms and R^(2a),R^(2b) and R^(2c) are hereinbefore defined may be prepared as shown inScheme 11. A 3-nitroaniline 37 where R^(2a), R^(2b) and R^(2c) arehereinbefore defined and ethyl(ethoxymethylene)cyano acetate 2 areheated at temperatures ranging from 60 to 190° C. either neat or in asolvent such as toluene followed by cyclization in a 3:1 mixture ofdiphenyl ether and biphenyl at all optimal temperature of 260° C. toprovide a mixture of 7-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile38a and 5-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile 38b which maybe separated by either recrystallization or chromatography. Heating of7-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile 38a with achlorinating agent selected from phosphorus oxychloride and oxalylchloride either neat or in a solvent such as methylene chloride,provides the corresponding 4-chloro-7-nitro-3-cyanoquinoline 39 followedby reaction with an aniline, phenol, thiophenol, amine, alcohol or thiolreagent of formula HX—(CH₂)n—R¹ 5 wherein R¹, X and n are hereinbeforedefined gives the 4-substituted 7-nitro-3-cyanoquinolines 40 whereR^(2a), R^(2b), R^(2c), R¹, X and n are hereinbefore defined and T and Zare carbon atoms. The condensation may be accelerated by heating thereaction mixture together with a catalytic amount or one equivalent ofpyridine hydrochloride or by using bases such as triethylamine,4-dimethylaminopyridine, diazabicyclo[5.4.0]undec-7-ene or sodiumhydride in an inert solvent, such as tetrahydrofuran, or sodium orpotassium alkoxides in an inert solvent, or in the absence of solvent.The nitro group may be reduced with iron and ammonium chloride inmethanol and water, or with iron and acetic acid in methanol to give the3-cyanoquinolines of Formula (V).

Scheme 12 shows an alternate route for the preparation of compounds ofFormula (V). Reaction of a 3-nitroaniline 37 where R^(2a), R^(2b) andR^(2c) are hereinbefore defined with acetic anhydride (Ac₂O) in watergives the corresponding acetamide 41. Reaction of the acetamide 41 withiron and ammonium chloride in methanol and water yieldsN-(3-aminophenyl)acetamide 42 which may be further reacted withethyl(ethoxylmethylene)cyano acetate 2 with heating at temperaturesranging from 60 to 120° C. either neat or in an inert solvent whichincludes toluene followed by cyclization in a 3:1 mixture of diphenylether and biphenyl at an optimal temperature of 260° C. to provide amixture of N-(3-cyano-4-oxo-1,4-dihydro-7-quinolinyl)acetamide 43a andN-(3-cyano-4-oxo-1,4-dihydro-5-quinolinyl)acetamide 43b which may beseparated by either recrystallization or chromatography. Heating ofN-(3-cyano-4-oxo-1,4-dihydro-7-quinolinyl)acetamide 43a with achlorinating agent selected from phosphorus oxychloride and oxalylchloride either neat or in a solvent which includes methylene chloride,provides the corresponding N-(4-chloro-3-cyano-7-quinolinyl)acetamide 44followed by reaction with an aniline, phenol, thiophenol, amine, alcoholor thiol reagent of formula 5 HX—(CH₂)_(n)—R¹, wherein R¹, X and n arehereinbefore defined, followed by acid hydrolysis to give the3-cyanoquinolines of Formula (V). The condensation may be accelerated byheating the reaction mixture together with a catalytic amount or oneequivalent of pyridine hydrochloride or by using bases such astriethylamine, 4-dimethylaminopyridine, diazabicyclo[5.4.0]undec-7-eneor sodium hydride in an inert solvent, such as tetrahydrofuran, orsodium or potassium alkoxides in an inert solvent or in the absence ofsolvent.

Compounds of Formulae (V), (VI), and (VII) may be converted to compoundsof Formula (I) of the invention by additional, routes as shown inSchemes 13, 14, 15 and 16. As outlined in Scheme 13, reaction of theamino group bonded to a carbon atom of Formulae (V), (VI) and (VII)where T, Z, R^(2a), R^(2b), R^(2c), R¹, X and n are hereinbefore definedwith 2,5-dimethoxytetrahydrofuran 45 where A and R⁴ are hereinbeforedefined, in acetic acid or N,N-dimethylformamide containing4-chloropyridine hydrochloride at temperatures ranging from 70 to 110°C. affords compounds of formula I where R³ is pyrrole and T, Z, R^(2a),R^(2b), R^(2c), R¹, X A, R⁴ and n are hereinbefore defined.

Specifically as outlined in Scheme 14, reaction of the amino groupbonded to a carbon atom of Formulae (V), (VI) and (VII) where T, Z,R^(2a), R^(2b), R^(2c), R¹, X and n are hereinbefore defined may bereacted with furfuyl aldehyde 46 catalyzed by acids which includeAmberlite IR-120 in 2-ethoxyethanol to give the corresponding pyrrolecarboxaldehyde 47 which may be treated with an amine 31 of formulaHNR¹³R¹⁴ where R¹³ and R¹⁴ are hereinbefore defined, which may be eithera primary or secondary amine, in a solvent selected from methanol,dioxane, tetrahydrofuan and methylene chloride, with the optionaladdition of a cosolvent which includes N,N-dimethylformamide, in thepresence of a reducing agent such as sodium triacetoxyborohydride orsodium cyanoborohydride with the optional addition of a catalyst such asacetic acid to afford compounds of formula I where R³ is pyrrole, A isabsent, R⁴ is —(C(R⁹)₂)_(r)H and r is 0.

It should be noted that compounds of formula 47 are also compounds offormula I where R³ is pyrrole, A is absent, R⁴ is —(C(R⁹)₂)_(r)H and ris 0.

Alternatively, Scheme 15 shows that the pyrrole carboxaldehyde 47 may bereduced to alcohol 48 using a reducing agent such as sodium borohydride.The resulting alcohol 48 may then be converted to pyrrole 49 having aleaving group LG selected from Cl, Br, p-toluelnesulfonate (TsO),methanesufonate (MsO) and trifluoromethanesulfonate (TfO). For examplethe alcohol may be converted into the corresponding chloride by areagent such as thionyl chloride or phosphorus oxychloide in thepresence of pyridine, or by hydrogen chloride. The leaving group LG maythen be displaced by treatment with a primary or secondary amine offormula R¹³R¹⁴NH, 31 where R¹³ and R¹⁴ are hereinbefore defined, whichmay be either a primary or secondary amine to afford compounds offormula I where R³ is pyrrole, A is absent, R⁴ is —(C(R⁹)₂)_(r)H and ris 0.

It should be noted that compounds of formula 48 are also compounds offormula I where R³ is pyrrole, A is absent, R⁴ is —(C(R⁹)₂)_(r)H and ris 0.

As outlined in Scheme 16, reaction of the amino group bonded to a carbonatom of Formulae (V), (VI) and (VII) where T, Z, R^(2a), R^(2b), R^(2c),R¹, X and n are hereinbefore defined, with 2,5-dimethoxytetrahydrofuran50 in acetic acid or N,N-dimethylformamide containing 4-chloropyridinehydrochloride at temperatures ranging from 70 to 110° C. affords pyrrole51 where T, Z, R^(2a), R^(2b), R^(2c), R¹, X, and n are hereinbeforedefined. Compounds of formula 51 are also compounds of Formula I whereR³ is pyrrole, A is absent, R⁴ is —(C(R⁹)₂)_(r)H and r is 0. Furtherreaction of pyrrole 51 with paraformaldehyde and an amine 31 of formulaHNR¹³R¹⁴ as the hydrochloride, where R¹³ and R¹⁴ are hereinbeforedefined, which may be either a primary or secondary amine, in at solventselected from methanol, dioxane, tetrahydrofuran and methylene chloride,with the optional addition of a cosolvent which includesN,N-dimethylformamide affords pyrrole compounds of Formula I.

Scheme 17 shows an alternative route for the conversion of compounds ofFormulae (II), (III) and (IV) to compounds of Formula (I) of theinvention by initial reaction of compounds of Formulae (II), (III) and(IV), wherein the LG is bromo, with hexabutylditin, also known asbis(tributyltin), in N,N-dimethylformamide in the presence of a basesuch as triethylamine and a catalyst such astetrakis(triphenylphosphine)pallidium(0) at elevated temperatures,preferably around 100° C. to provide the corresponding tin derivative52. Reaction of 52 with bromo derivative 21 in a solvent such asN,N-dimethylformamide in the presence of a a catalyst such asdichlorobis(triphenylphosphine)pallidium(II) at elevated temperatures,provides compounds of Formula (I) of the invention wherein R¹, R^(2a),R^(2b), R^(2c), R³, R⁴, n, A, T, X, and Z are hereinbefore defined.

Scheme 18 shows an alternate route for the preparation of compounds ofFormula (I) from 29. The carboxaldehyde group of 29 may be reduced to analcohol 53 with a reducing agent such as sodium bomohydride. Theresulting alcohol 53 may then be converted to 54 which has a leavinggroup LG selected from Cl, Br, p-toluenesulfonate (TsO),methanesulfonate (MsO) and trifluoromethanesulfonate (TfO). For examplethe alcohol is converted into the corresponding chloride by a reagentsuch as thionyl chloride or phosphorus oxychloride in the presence ofpyridine, or by hydrogen chloride. The alcohol may also be converted tothe chloride with 1-chloro-N,N, 2-trimethylpropenylamine in the presenceof pyridine. The leaving group LG may then be displaced by treatmentwith a primary or secondary amine of formula R¹³R¹⁴NH, 31, where R¹³ andR¹⁴ are hereinbefore defined, which may be either a primary or secondaryamine to afford compounds of Formula (I) of the invention wherein R¹,R^(2a), R^(2b), R^(2c), R³, R¹³, R¹⁴, n, T, X, and Z are hereinbeforedefined, A is absent and R⁴ is —C((R⁹)₂)_(r)H where r is 0.

Scheme 19 shows a route for the conversion of compounds of Formulae(II), (III) and (IV) to compounds of Formula (I) of the invention byreaction of compounds of Formulae (II), (III) and (IV), wherein the LGis bromo, with bromo derivative 21 in the presence of hexamethylditinand a catalyst such as tetrakis(triphenylphosphine)pallidium(0) indioxane at elevated temperatures to provide compounds of Formula (I) ofthe invention wherein R¹, R^(2a), R^(2b), R^(2c), R³, R⁴, n, A,T, X, andZ are hereinbefore defined.

Scheme 20 depicts the preparation of compounds of Formula (I) of theinvention whereby compounds of Formulae (II), (III) and (IV), whereinthe LG is bromo, may be reacted with bromo containing aldehydes ofstructure 55 in the presence of hexamethylditin and a catalyst such astetrakis(triphenylphosphine)pallidium(0) in dioxane at elevatedtemperatures to provide compounds of structure 29. Aldehyde 29 may betreated with an amine 31 of formula HNR¹³R¹⁴ in a solvent selected frommethylene chloride, dioxane and tetrahydrofuran in the presence of areducing agent such as sodium triacetoxyborohydride or sodiumcyanoborohydride with the optional addition of a catalyst which includesacetic acid and the like to provide compounds of Formula (I) of theinvention wherein R¹, R^(2a), R^(2b), R^(2c), R³, R¹³, R¹⁴, n, T, X, andZ are hereinbefore defined, A is absent and R⁴ is —C((R⁹)₂)_(r)H where ris 0.

Standard Pharmacological Test Procedures

Evaluation of representative compounds of this invention in severalstandard pharmacological test procedures indicated that the compounds ofthis invention possess significant antiproliferative activity and areinhibitors of protein tyrosine kinases. Based on the activity shown inthe standard pharmacological test procedures, the compounds of thisinvention are therefore useful as antineoplastic agents. In particular,these compounds are useful in treating, inhibiting the growth of, oreradicating neoplasms such as those of the breast, kidney, bladder,mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver,prostate and skin.

In addition to having antineoplastic properties, the compounds of thepresent invention are expected to be useful in treating a variety ofprotein tylosine kinase associated disorders including, but not limitedto, osteoporosis, osteoarthritis, restenosis, atherosclerosis,fibroplasia, angiofibromas, hemangiomas, diabetes, acute and chronicnephropathies, Kaposi's sarcoma, atheroma, neovascular glaucoma,neovascularization associated with macular degeneration, rheumatoidarthritis, psoriatic arthritis, transplant rejection, T-cell mediatedhypersensitivity diseases, including gluten-sensitive eniteropatily(Celiac disease), contact and delayed-type hypersensitivity, psoriasis,contact dermatitis, protection from ischemic or reperfusion injury suchas that incurred during organ transplantation, stroke or myocardialinfarction, transplantation tolerance induction, lupus, graft versushost disease, glomerulonephritis, serum sickness, respiratory and skinallergies, autoimmune alopecia, pernicious anemia, Hashimoto'sthyroiditis, autoimmune hyperthyroidism, Addison's disease, multiplesclerosis, inflammatory bowel disease, acute inflammatory responses (forexample acute respiratory distress syndrome), Behcet's disease, atopicdermatitis, systemic sclerosis and eczema.

The test procedures used and results obtained are shown below.

c-Src Kinase Assay

Inhibitors of Src (partially purified preparation purchased from UpstateBiotechinologies) tyrosine kinase activity are analyzed in an ELISAformat. The Boehringer Mannheim Tyrosine Kinase Assay Kit (Catalognumber 1-534505) with a cdc2 substrate peptide containing Tyr15 is usedfor the assay. Horseradish Peroxidase (HRP)-conjugatedanti-phosphotyrosine is used to detect phosphorylated peptide via acolor reaction. Conditions recommended by the manufacturer are employed.

Reaction conditions: Five micmoliter aliquots of each compound preparedfresh at the time of the assay are added as a solution in 10 mM HEPES pH7.5, 10% DMSO to the reaction well. Thirty-five microliters of reactionmix containing Src, bluffer and peptide/bovine serum albumin mix areacided to the compound wells and incubated at 30° C. for 10 minutes(reaction buffer: 50 mM TrisHCl pH 7.5, 10 nM MgCl₂, 0.1 mM ECTA, 0.5 mMNa₃VO₄). The reaction is started by addition of 10 microliters of ATP,incubated at 30° C. for 1 hour, and stopped by addition of 20microliters of 0.5M EDTA. The reaction mixture with the phosphorylatedpeptide is then transferred to a streptavidin-coated microtiter plate(provided in the kit) and allowed to bind for 20 minutes. Unboundpeptide and reaction mixture is decanted and the plate is washed withPBS six times. HRP-conjugated phosphotyrosine antibody supplied in thekit is incubated with the plate for one hour, then decanted. The plateis again washed with PBS six times. Substrate (provided in the kit) isadded and absorbance at 405 nm is measured.

Activity is determined as % inhibition as calculated by the formula:(1−Abs/Abs(max)×100% inhibition. Where multiple concentrations of thetest agent are used, an IC₅₀ (concentration which gives 50%. inhibition)may be determined. The results obtained for representative compounds ofthis invention are listed in Table 1. Multiple entries for a givencompound indicate that it is tested multiple times.

Anchorage Independent Src-transformed Fibroblast Proliferation Assay

Rat2 fibroblasts stably transformed with a plasmid containing a CMVpromotor controlled v-Src/-Hu c-Src fusion gene in which the catalyticdomain of human c-Src was inserted in place of the v-Src catalyticdomain in the v-Src gene are used for the measurement of src dependentsuspension growth. Ultra-low cluster plates (Costar #3474) are seededwith 10,000 cells per well on Day 1. Compound is added in serialtwo-fold dilutions from 10 micromoar to 0.009 micromolar on Day 2 andMTS reagent (Promega) is added on Day 5 (100 microliters of MTS/mediummix+100 microliters of medium already on the cells and the absorbance ismeasured at 490 nm. The results are analyzed as follows to yield an IC₅₀for proliferation (micromolar units) as follows: % inhibition=(Abs490 nmsample−blank)/(Abs490 nm no cmpd control−blank)×100%. The resultsobtained for representative compounds of this invention are listed inTable 1. Multiple entries for a given compound indicate that it wastested multiple times.

TABLE I ELISA anch-indep c-src src-tx fib Example IC₅₀ nM IC₅₀ μM 1 25 22 0.27, 0.19, 0.13 3 11 10, 4.1 4 14 5 4.3 0.20 6 4 1.60 9 6 2.70 10 2.40.90 11 43 >10 12 77 >10 13 10.4, 4.0 1.51, 1.59 14 40% at 1 μM 1563 >10 16 44 >10 17 0.7, 2.1, 3.1 0.31 18 180 19 2.0, 1.7 0.16 20 1.1,0.8 0.04, 0.03 21 40/9.0 1.7/4.7 22 6.8 0.60 23 2.0 0.09 24 2.1, 3.70.5, 0.15, 0.18, 0.18 25 3.6, 6.0, 4.9 1.3, 0.93 26 24 27 8.0, 18, 11.02 28 25 4.10 29 4.1, 2.5 0.54, 0.50 30 4.4, 1.5 0.03, 1.10, 0.82 318.3, 5.6 0.08, 2.07, 1.93 32 2.7 2.0, 1.9 34 3 36 1.9 0.16, 0.20 37 191.59, 1.49 38 81 12.7, 10.6 39 220 40 10 41 2.4 0.38 42 2.7 43 1.7 44 2545 51 46 0.61 0.16 47 1.1 1.17 49 13 1.68 50 111 51 8.2 0.42 52 11 532.9 0.25 54 62 >10 55 0.73 0.22 57 0.9 0.05 58 11 5.1 59 12, 15 64950 >10 65 200 >10 66 380 >10 67 3.0. 4.9 0.11 68 1.5 0.12 69 110 >10 7025 6.0 71 26, 24 6.8 72 78 >10 73 58, 75 >10 74 40 1.40 75 24 0.29 76 221.1 77 21 0.42 78 1.3 0.14 79 1.7 0.13 80 1.5 0.08 81 1.1 0.13 82 0.480.05 83 42 3.90 84 7.5 0.77 85 36, 41 10.2 86 1.1 0.21 87 0.46 0.22 883.0 0.85 89 0.52, 0.84 0.09 90 10% at 100 nM >10 91 3.1 >10 92 8.6 2.1193 610, 680 >10 96 240 99 44 >10 100 0.57 0.34, 0.40 101 15 >10 102 187.5 103 4.3, >10 104 14 0.56 105 10 >10, 5.9, >10 111 410 >10 112 36 7.3113 10 1.4 114 2,200 >10 115 5,000 >10 116 25% at 10 μM >10 117 210,160, 120 6.9 118 160 3.0 119 130 >10 120 170 >10 121 4.8, 1.8 >10 12244% at 10 μM 128 3.2 0.64 131 2.0 0.09 133 7.0 0.73 139 300, 340 >10 140240, 200 >10 141 750 >10 142 31 >10 143 26 >10 144 4.0 0.092 145 17% at10 nM >10 146 22 6.5 147 0.47 4.6 148 8.6 2.1 149 0.67 2.5 150 13, 6.60.50, 0.52 151 4.7 0.34, 0.49, 0.20 152 4.8, 3.8 153 2.8, 2.7 162 76 >10163 >1,000 >10 164 >1,000 >10 165 28% at 10 nM >10 166 5.5 0.72 167 12,16 0.9 174 95 5.6 176 1.7 0.09 177 0.69 2.1, 0.88 179 0.23 0.27 185 3.40.46. 8.3, >10 186 30 >10 188 0.86 0.07, 0.13 192 2.1 0.17 193 34 >10194 12 >10 197 4.4 0.34, 0.20, 0.73 198 1.9 0.24, 0.84, 0.14 200 1.40.25, 0.73 204 6.4 1.1 218 3.1, 45 0.6 226 31 227 25 228 46 >10 229 2.30.45 230 0.63, 2.52, 7.1 0.064, 0.22, 0.14 231 6.8 0.39 232 78 3.5 23328 234 7.2 0.72 235 4.1 0.79 236 3.0 0.57 237 0.18, 0.55, 0.18 0.49,0.52, 0.41

Raf1 Kinase Cascade Assay Procedure

Raf-1 (c-Raf) is used to phosphorylate and activate inactive GST-MEK1which then can phosphorylate and activate inactive p42 GST-MAPK, whichsubsequently is measured for phosphorylation of the TEY sequence (aa's202-204) by a phospho-specific antibody from Sigma (cat. #77439219041)Reagents: Sf9 insect cell lysate containing full length 6his-taggedrecombinant human c-Raf. (Specific Activity: ˜200 U/ml). HumanNon-active Mek-1-GST and human GST-MAP kinase (recombinant proteinsproduced in E. coli).

Stock Solutions Raf Assay:

Assay Dilution Buffer (ADB): 20 mM MOPS, pH 7.2, 25 mM β-glycerolphosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol.

Magnesium/ATP Cocktail: 500 μM cold ATP and 75 mM magnesium chloride inADB.

Active Kinase: Human Active c-Raf: Use at 0.4 U per assay point.

Non-active GST-MEK1: Use at 0.1 μg per assay point.

Non-active GST-p42 MAP Kinase: Use at 1.0 μg per assay point.

Stock Solutions ELISA:

TBST—Tris (50 mM, pH 7.5), NaCl (150 mM), Tween-20 (0.05%)

Superblock (Pierce)

Anti-GST Ab (Pharmacia)

Anti-Phospho MAPK (Sigma)

Anti-Mouse Ab/Europium conjugate (Wallac)

Assay Procedure:

First Stage: c-Raf Dependent Activation of GST-MEK and GST-MAPK

Add 20 ml of ADB per assay (i.e. per well of a 96 well plate)

Add 10 ml of 0.5 mM cold ATP and 75 mM magnesium chloride in ADB.

Add 2 ml of c-Raf (0.4 U/assay), in conjunction with 1.6 ml non-activeMEK1 (0.4 mg/assay).

Add 4 ml of non-active GST-p42 MAP Kinase (1.0 mg/assay).

Incubate for 60 minutes at 30° C. in a shaking incubator.

Transfer this mixture to an anti-GST Ab coated 96 well plate (NuncImmunosorb plates coated o/n with a-GST, then blocked with PierceSuperblock).

Incubate for 60 minutes at 30° C. in a shaking incubator

Wash 3× with TBST, add Anti-Phospho MAPK (Sigma) (1:3000)

Incubate for 60 minutes at 30° C. in a shaking incubator

Wash 3× with TBST, add Anti-Mouse Ab/Europium conjugate (Wallac) (1:500)

Incubate for 60 minutes at 30° C. in a shaking incubator

Wash 3× with TBST, Read plates in Wallac Victor model Plate Reader.

Collect data analyze in Excel for single point and IC50 determinations.

Single point assay—% inhibition at 10 mg/ml (% Inhibition=1−cpd.treatedsample/untreated control). IC₅₀ determinations—done on compounds fromsingle point assays with >80% inhibition. Typically Raf-1 assay is runat compound concentrations from 10 μM to 30 nM in half log dilutions. (%inhibition is determined for each compound concentration). The resultsobtained for representative compounds of this invention are listed inTable 2.

Cell Based Screen for Inhibitors of Raf Kinase

Materials

Cell Lines: Human adenocarcinoma cell line LoVo which is known to begrowth inhibited by low nM concentrations of a reference standardinhibitor of Ras and human adenocarcinoma cell line CaCo-2, which isknown to be growth resistant to the same reference compound.

Cell Media: RPMI 1640 with 10% Fetal Bovine Serum supplemented withL-glutamine and Pennicilin/Streptomycin.

Compounds: Supplied usually as a 10 mM stock in 100% DMSO.

Normal Saline: 150 mM NaCl

Trichloroacetic Acid (TCA): 50% (w/v) in water

Sulforhodamine B (SRB): 0.4% (w/v) in 1% Acetic Acid

Tris Base: 10 min in water

Methods

Cells are plated at 2000 cells per well for cell line LoVo and 1500cells for cell line CaCo-2 in 96 well plates. Cells are plated in media(200 μl) and allowed to adhere overnight at 37° C. At 24 hours postplating, compounds are added directly at a volume of 0.5 μl. For thequalitative screen (compounds screened at 25 μM) compound is addeddirectly to cells. For the quantitative screen, compound is firstdiluted in DMSO to generate concentrations of compound or referencestandard of: 1, 5, 10 and 25 μM. It is advisable to make the dilutionsin an identical 96 well plate so that compounds may be added using amultichannel micropipettor set at 0.5 μl. The cells are then incubatedfor four days after which the media is removed using a 12 well manifoldby first tipping the plate forward at a 45 degree angle and theninserting the manifold in an upright orientation to prevent the tips ofthe manifold from disturbing cells it the bottom of the plate. 200 μl ofnormal saline is then added to each well using an 8 well multichannelpipettor, followed by the careful addition of 50 μl of 50% TCA. Theplates are then incubated for 2 hours at 4° C., after which thesupernatant is removed using the same technique as above and the platedwashed twice with 200 μl water. The plates are then air dried and 50 μlof SRB stock solution is carefully added so that the entire bottom ofeach well is covered. This again may be used using an 8 wellmultichannel pipettor. The SRB is incubated with fixed cells for 15minutes at room temperature after which the SRB is removed with themanifold as described above and the plates washed twice with 350 μl of1% acetic acid per well each time. The plates are then air dried afterwhich the bound SRB is released from protein by the addition of 200 μlof Tris base. Resolubilizing the SRB is aided by placing the plates on arotator for 15-30 minutes. The absorbance of each well is determined at550 or 562 nm using a microtiter plate reader.

Each compound or dilution thereof is performed in triplicate. Outliersare identified by visual inspection of the data. Each plate should havea “0” control (vehicle only).

Qualitative screen: To calculate % inhibition of a compound at 25 μM,the following formula is used: 1-(experimental absorbance @ 25 μMcompound/“0” control absorbance)×100=% inhibition at 25 μM. Compoundshaving >50% inhibition at 25 μM are placed in the quantitative assay.

Quantitative Assay: A standard curve is constructed by plotting theconcentration of compound against the average absorbance calculated atthat concentration. A curve is plotted and the concentration at whichthe curve passes through the 50% the absorbance mark seen in the “0”control well is the IC₅₀ calculated for that compound. Multiple entriesfor a given compound indicate that it was tested multiple times. Theresults obtained for representative compounds of this invention in Table2.

TABLE 2 raf LoVo CaCo-2 Example IC₅₀ nM IC₅₀ μM IC₅₀ μM  7 8.0 3.7 >10 8 6.0 >10 >10  33 6.0 0.006 1.9, 0.78  35 22, 4.0, 13 <0.005,<0.005, >10 <0.005, 0.006  48 90  56 1.0 0.29, 0.44, 0.31 1.0, 1.0, 0.6 62 27  63 5.0 3.8 2.2  94 89  95 40  97 16 0.033 >1  98 10 0.0071 0.64106 9.2 0.0064 >1 107 8.0 0.025 >1 108 1.5 0.0026 0.39 109 5.4 0.00680.98 110 4.3 0.01 >1 123 80 0.04 1.5 124 33 0.15, 0.03 1.2, 2.9 125 4.00.02, 0.015 1.9, 2.8 126 20 0.075 >1 127 180 129 7.0 0.042 >1 132 300,330 0.43 7.0 134 80 0.0046 >1 135 9.0, 10 0.0068 >1 136 2.5, 1.80.011 >1 137 90 0.0485 >1 138 5.6 0.0062 0.81 154 9.0, 11 0.0068 >1 15520 156 9.0, 12 0.0056 1 157 9.0, 5.0 0.0245 >1 159 2.0 0.0042 0.71 1603.8 0.0041 0.62 161 4.0 0.0056 >1 168 27.28 2.0 4.6 169 8.0 0.04, 0.0470.6, 1.4 170 30 0.05 >10, 5 171 10 0.008, 0.005, <0.005, <0.005 2.2,2.7, >1 172 7.4 0.0079 >1 173 22 0.025 >1 175 8.0 0.33 >1 178 4,000 1803.7 0.0056 0.93 181 80 182 >10,000 183 1,500 184 1,400 187 1.0, 5.00.008, 0.009, 0.018, 0.0077, >10, >10, 5.5 0.0096, 0.0126, 0.007, 0.009189 2.7 0.006 1.25 190 0.9 0.002 >10, >1 191 1.0 0.03 >10 195 3.0, 2.00.0023, 0.002, 0.0022, 0.47, 0.43, 0.0037, 0.005, 0.0027, 0.0033, 0.00280.77. 0.71, 0.85, >1, >1 196 2.8 <0.005, 0.0029 1.1, 0.55 199 170.0095 >1, >1 201 5.0, 7.5 0.0084 >1 202 4.5, 13 0.0065 >1 203 220.0097 >1 205 27 0.275 0.94 206 28 0.28 >1 207 8,000 208 8,100 209 1,900210 1.8 0.0032 0.59 211 6.0 0.0053 >1 212 2.0 0.004 0.78 213 400.0452 >1 214 2.5 0.0057 >1 215 2.3 0.0035 >1 216 2.0 0.007 >1 217 8.00.036 >1 219 32 0.015 >1 220 14 0.0077 >1 221 12 0.074 >1 221 120.074 >1 135 30 238 45 239 48 240 42 241 13 243 18 244 48 245 18 246 28247 20 248 190 249 180 250 190 251 190 252 200 253 180 254 40 255 180256 190 257 150 258 140 259 50 260 20 261 15 262 24 263 17 264 160 26514 266 9 267 35 268 35 269 9 270 180 271 210 422 40 439 15 448 21 450 19452 23 456 17 460 55 462 50 463 27

Based on the results obtained for representative compounds of thisinvention, the compounds of this invention are antineoplatic agentswhich are useful in treating, inhibiting the growth of, or eradicatingneoplasms. In particular, the compounds of this invention are useful intreating, inhibiting the growth of, or eradicating neoplasms that eitherexpress Src or raf or neoplasms that depend at least in part on the Srcor raf pathways. Such neoplasms include those of the breast, kidney,bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung,pancreas, skin, liver, prostate or brain. Based on the results obtained,the compounds of this invention are also useful in the treatment ofosteoporosis.

As may be appreciated from the data in Tables 1 and 2, the compoundsaccording to the invention are endowed with valuable biologicalproperties useful in the treatment of certain diseases that are theresult of deregulation of protein kinases.

The compounds of this invention may be formulated neat or may becombined with one or more pharmaceutically acceptable carriers foradministration. For example, solvents, diluents and the like, and may beadministered orally in such forms as tablets, capsules, dispersiblepowders, granules, or suspensions containing, for example, from about0.05 to 5% of suspending agent, syrups containing, for example, fromabout 10 to 50% of sugar, and elixirs containing, for example, fromabout 20 to 50% ethanol, and the like, or parenterally in the form ofsterile injectable solution or suspension containing from about 0.05 to5% suspending agent in an isotonic medium. Such pharmaceuticalpreparations may contain, for example, from about 0.05 up to about 90%of the active ingredient in combination with the carrier, more usuallybetween about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 1000 mg/kgof animal body weight, optionally given in divided doses two to fourtimes a day, or in sustained release form. For most large mammals thetotal daily dosage is from about 1 to 1000 mg, preferably from about 2to 500 mg. Dosage forms suitable for internal use comprise from about0.5 to 1000 mg of the active compound in intimate admixture with a solidor liquid pharmaceutically acceptable carrier. This dosage regimen maybe adjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

The compounds of this invention may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

In some cases it may be desirable to administer the compounds directlyto the airways in the form of an aerosol.

The compounds of this invention may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt may be prepared inwater suitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparation contain a preservative to prevent thegrowth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier may be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

For the treatment of cancer, the compounds of this invention may beadministered in combination with other antitumor substances or withradiation therapy. These other substances or radiation treatments may begiven at the same or at different times as the compounds of thisinvention. These combined therapies may effect synergy and result inimproved efficacy. For example, the compounds of this invention may beused in combination with mitotic inhibitors such as taxol orvinblastine, alkylating agents such as cisplatin or cyclophosamide,antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalatorssuch as adriamycin or bleomycin, topoisomerase inhibitors such asetoposide or camptothecin, antiangiogenic agents such is angiostatin,and , antiestrogens such is tamoxifen.

As used in accordance with this invention, the term providing aneffective amount of a compound means either directly administering suchcompound, or administering a prodrug, derivative, or analog which willform an effective amount of the compound within the body.

The invention will be more fully described in conjunction with thefollowing specific examples which are not to be construed as limitingthe scope of the invention.

REFERENCE EXAMPLE 1 6-Bromo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile

A solution of 5-bromoanthranilic acid (21.6 g, 100 mmol) anddimethylformamide dimethylacetal (50 mL) in dimethylformamide (150 mL)was heated at 155-160° C. for 8 hours then cooled to room temperature.The volatiles were removed in vacuo to provide 28.5 g of theintermediate amidine.

Lithium diisopropylamide (LDA) was generated from isopropylamine (9.84mL, 70.2 mmol) and 2.5 M n-butyl lithium (29.5 mL, 70.2 mmol) intetrahydrofuran (150 ml) at −78° C. Acetonitrile (3.67 mL, 70.2 mmol)was added and the resulting white suspension was stirred at −78° C. for1 hour. A solution of 10 g of the amidine in 100 mL of tetrahydrofuranwas added and stirring was continued for 1 hour at −78° C. and then 1hour at room temperature. The reaction was quenched by addition ofacetic acid (15 mL). The volatiles were removed in vacuo and water wasadded to the residue. The aqueous solution was basified to pH 9 by theaddition of ammonium hydroxide. The white precipitate was collected,suspended in methylene chloride and filtered to provide6-bromo-4-oxo-1,4-dihydro-quinoline-3-carbonitrile as a white solid;

¹H NMR (DMSO-d₆) δ 7.60 (d, J=9 Hz, 1H), 7.93 (dd, J=9, 2 Hz, 1H), 8.20(d, J=2 Hz, 1H), 8.77 (s, 1H); MS (ES) m/z 248.7 (M+1). Analysis forC₁₀H₅BrN₂O: Calcd: C, 48.22; H, 2.02; N, 11.25; Br, 32.08. Found: C,48.18; H, 2.18; N, 11.24; Br, 32.09.

REFERENCE EXAMPLE 2 6-Bromo-4-chloro-3-quinolinecarbonitrile

A mixture of 6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (1.3 g,4.86 mmol) and 8 mL of phosphorous oxychloride was heated at reflux for30 minutes. The dark brown solution was cooled to room temperature and10 mL of hexane was added. The resultant solid was collected byfiltration washing with hexane, water, and hexane to provide 1.05 g of6-bromo-4-chloro-3-quinolinecarbonitrile as a tan solid;

¹H NMR (DMSO-d₆) δ 8.12 (d, J=9 Hz, 1H), 8.19 (dd, J=9, 2 Hz, 1H), 8.45(d, J=2 Hz, 1H), 9.23 (s, 1H); MS (ES) m/z 267.1, 269.0 (M+1). Analysisfor C₉H₄BrClN₂: Calcd: C, 44.90; H, 1.51; N, 10.47. Found: C, 44.53; H,1.63; N, 10.27.

REFERENCE EXAMPLE 36-Bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

A mixture of 2,4-dichloro-5-methoxy aniline (prepared by the proceduredescribed in WO 8501939-A1) (730 mg, 3.77 mmol) and sodium hydride (180mg of a 60% dispersion in oil, 4.5 mmol) in 30 mL of tetrahydrofuran washeated at reflux for 1 hour. The mixture was cooled,6-bromo-4-chloro-3-quinolinecarbonitrile (600 mg, 2.24 mmol) was addedand the mixture was heated at reflux for 50 minutes. After cooling toroom temperature, the reaction mixture was partitioned between ethylacetate and saturated sodium bicarbonate. The organic layer was washedwith saturated sodium chloride, dried over magnesium sulfate, filteredand concentrated in vacuo. The resultant solid was purified by flashchromatography eluting with a gradient of 3:1 to 1:1 hexane:ethylacetate to provide 530 mg (53% yield) of6-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile as tancrystals, mp 232-234° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.89 (s, 3H), 7.58 (s, 1H), 7.88(s, 1H), 8.01 (d, J=7 Hz, 1H), 8.30 (dd, J=7, 2 Hz, 1H), 9.12 (d, J=2Hz, 1H), 9.29 (s, 1H); MS (ES) m/z 424.2 (M+1). Analysis forC₁₇H₁₀BrClN₃O: Calcd: C, 48.26; H, 2.38; N, 9.93. Found: C, 48.36; H,2.45; N, 9.88.

REFERENCE EXAMPLE 4 7-Bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A mixture of ethyl(ethoxymethylene)cyanoacetate (30 g, 180 mmol) and3-bromoaniline (25.0 g, 145 mmol) in 300 mL of toluene was heated atreflux for 7 hours. Upon cooling to room temperature a white solidformed. The solid was collected by filtration washing with toluene. Theolefin (30.0 g, 101 mmol) was dissolved in 600 mL of a 3 to 1 mixture ofdiphenyl ether and biphenyl and the solution was heated at 259-260° C.(internal temperature) with the ethanol formed in the reaction removedby distillation. After heating overnight, the solution was cooled toroom temperature and poured into hexane. The precipitate was collectedto provide 22.0 g of a solid that was combined with 275 mL ofdimethylformamide, heated at 100° C. and then filtered to provide 9.0 g(36% yield) of 7-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile;

¹H NMR (DMSO-d₆) δ −7.64 (dd, J=9, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H), 8.04(d, J=9 Hz, 1H), 8.78 (s, 1H); MS (ES) m/z 248.8 (M+1). Analysis forC₁₀H₅BrN₂O: Calcd: C, 48.22; H, 2.02; N, 11.25. Found: C, 48.31; H,1.93; N, 11.33.

REFERENCE EXAMPLE 5 7-Bromo-4-chloro-3-quinolinecarbonitrile

To suspension of 7-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (1.0g, 4.02 mmol) in methylene chloride was added oxalyl chloride (1.75 mL,20 mmol) followed by dimethylformamide (78 μL, 1.00 mmol). The mixturewas stirred at room temperature for 3 hours and additional oxalylchloride (1.75 mL, 20 mmol) and dimethylformamide (78 μL, 1.00 mmol)were added. The reaction mixture was stirred at room temperatureovernight and then diluted with methylene chloride. Ice water was addedand the aqueous layer was basified to pH 9 with sodium carbonate. Theorganic layer was washed with water, dried over magnesium sulfate,filtered and concentrated in vacuo to provide 1.0 g (93% yield) of7-bromo-4-chloro-3-quinolinecarbonitrile as a light yellow solid;

¹H NMR (DMSO-d₆) δ 8.07 (dd, J=9, 2 Hz, 1H), 8.26 (d, J=9 Hz, 1H), 8.46(d, J=2 Hz, 1H), 9.22 (s, 1H); MS (ES) m/z 268.7 (M+1). Analysis forC₁₀H₄BrClN₂: Calcd: C, 44.90; H, 1.51; N, 10.47; Br, 29.87; Cl, 13.25.Found: C, 45.00; H, 1.76; N, 10.40; Br, 30.25; Cl, 13.47.

REFERENCE EXAMPLE 67-Bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile

A mixture of 2,4-dichloroaniline (1.213 g, 7.49 mmol) and sodium hydride(300 mg of a 60% dispersion in oil, 7.50 mmol) in 50 mL oftetrahydrofuran was heated at reflux for 15 minutes. The mixture wascooled, 7-bromo-4-chloro-3-quinolinecarbonitrile (1.00 g, 3.75 mmol) wasadded and the mixture was heated at reflux for 30 minutes. After coolingto room temperature the reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo. The resultant solid was purified byflash silica gel chromatography eluting with 3:1 hexane:ethyl acetate toprovide 927 mg (63% yield) of7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile as a lightyellow solid, mp 180-183° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 7.53-7.65 (m, 1H), 7.83 (d, J=2Hz, 1H), 7.93-7.99 (m, 2H), 8.13 (d, J=2 Hz, 1H), 8.53 (d, J=9 Hz, 1H),8.83 (s, 1H); MS (ES) m/z 392, 394, 396 (M+1). Analysis forC₁₆H₈BrCl₂N₃: Calcd: C, 48.89; H, 2.05; N, 10.69. Found: C, 48.53; H,2.18; N, 10.61.

REFERENCE EXAMPLE 77-Bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitrile

A mixture of 7-bromo-4-chloro-3-quinolinecarbonitrile (5.0 g, 18.69mmol), 4-chloro-2-fluoroaniline (3.27 g, 22.43 mmol) and pyridinehydrochloride (2.2 g 18.69 mmol) in 150 mL of ethoxyethanol was heatedat reflux for 4 hours. After cooling, the solvent was removed in vacuoand the residue was diluted with ice water, basified (pH 9) withammonium hydroxide, and extracted into ethyl acetate. The extracts werewashed with saturated sodium chloride, dried over sodium sulfate andconcentrated. The residue was treated with diethyl ether, and the yellowsolid was collected by filtration. The filtrate was concentrated andpurified by flash silica gel chromatography eluting with methylenechloride:diethyl ether:methanol (9:1:0.1) to provide 3.0 g (43%) of7-bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitrile as a lightbrown solid;

¹NMR (DMSO-d₆) δ 7.38 d, J=9 Hz, 1H), 7.47-7.53 (m, 1H), 7.62 (dd, =3, 9Hz, 1H), 7.84 (d, J=9 Hz, 1H), 8.13 (s, 1H), 8.44 (d, J=9 Hz, 1H), 8.62(s, 1H); MS (ES) m/z 377.7 (M+1). Analysis for C₁₆H₈BrClFN₃: Calcd: C,51.03; H, 2.14; N, 11.16. Found: C, 50.67; H, 2.20; N, 11.02.

REFERENCE EXAMPLE 87-Bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

A mixture of 2,4-dichloro-5-methoxy aniline (prepared by the proceduredescribed in WO 8501939-A1) (202 mg, 1.05 mmol),7-bromo-4-chloro-3-quinolinecarbonitrile (267 mg, 1.0 mmol) and pyridinehydrochloride (20 mg) in 10 mL of ethoxyethanol was heated at reflux for1.5 hours, and concentrated. The residue was treated with saturatedsodium bicarbonate. The solids were filtered and dried. The product wasthen dissolved in ethyl acetate and filtered through hydrous magnesiumsilicate. The filtrate was concentrated, and the resulting solids weretriturated with a small quantity of ethyl acetate to give the first cropof product as a yellow solid. The filtrate was purified by flash silicagel chromatography, eluting with 1:1 hexane:ethyl acetate to give asecond crop of product, providing a total of 216 mg (51% yield) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile as ayellow solid, mp 192-193° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.91 (s, 3H), 7.59 (s, 1H), 7.86(s, 1H), 8.15 (dd, J=9, 2 Hz, 1H), 8.26 (d, J=2 Hz, 1H), 8.74 (d, J=9Hz, 1H), 9.28 (s, 1H); MS (ES) m/z 424.0 (M+1). Analysis forC₁₇H₁₀BrCl₂N₃O: Calcd: C, 48.26; H, 2.38; N, 9.93. Found: C, 48.06; H,2.53; N, 9.71.

REFERENCE EXAMPLE 9 4-(4-Benzylanilino)-7-bromo-3-quinolinecarbonitrile

A mixture of 4-aminodiphenylmethane (604 mg, 33 mmol)7-bromo-4-chloro-3-quinolinecarbonitrile (800 mg, 3.0 mmol) and pyridinehydrochloride (30 mg) in 15 mL of ethoxyethanol was heated at reflux for1 hour. The mixture was cooled, poured into 5% sodium carbonatesolution, and stirred. The product was filtered, washed with water, anddried to provide 1.20 g (96% yield) of4-(4-benzylanilino)-7-bromo-3-quinolinecarbonitrile as a tan solid, mp195-197° C.;

¹H NMR (DMSO-d₆) δ 3.99 (s, 2H), 7.26 (m, 9H), 7.81 (dd, J=9, 2 Hz, 1H),8.12 (d, J=2 Hz, 1H), 8.41 (d, J=9 Hz, 1H), 8.57 (s, 1H), 9.91 (s, 1H);MS (ES ) m/z 416.1 (M+1). Analysis for C₂₃H₁₆BrN₃: Calcd: C, 66.68; H,3.89; N, 10.14. Found: C, 66.67; H, 3.96; N, 9.81.

REFERENCE EXAMPLE 107-Bromo-4-(4-phenoxyanilino)-3-quinolinecarbonitrile

A mixture of 4-phenoxyaniline (204 mg, 1.1 mmol),7-bromo-4-chloro-3-quinolinecarbonitrile (267 mg, 1.0 mmol) and pyridinehydrochloride (20 mg) in 10 mL of ethoxyethanol was heated at reflux for1 hour. The mixture was cooled, poured into 5% sodium carbonatesolution, and stirred. The product was filtered, washed with water, anddried to provide 396 mg (95% yield) of7-bromo-4-(4-phenoxyanilino)-3-quinolinecarbonitrile as a tan solid, mp205-207° C.;

¹H NMR (DMSO-d₆) δ 7.05 (m, 4H), 7.10 (t, J=7 Hz, 1H), 7.27 (dd, J=7, 2Hz, 2H), 7.37 (m, 2H), 7.72 (dd, J=9, 2 Hz, 1H), 8.01 (d, J=2 Hz, 1H),8.41 (t, J=4 Hz, 2H), 10.02 (s, 1H); MS (ES) m/z 416.1 (M+1). Analysisfor C₂₂H₁₄BrN₃O: Calcd: C, 63.48; H, 3.39; N, 10.09. Found: C, 63.12; H,3.29; N, 10.00.

REFERENCE EXAMPLE 11 Ethyl 2-Cyano-3-(3-iodophenylamino)acrylate (E/Z1:1)

A mixture of 3-iodoaniline (5.0 g, 22.83 mmol) andethyl(ethoxymethylene)cyanoacetate (3.86 g, 22.83 mmol) was heated at120° C. for 30 minutes. The resultant solid mixture was cooled to roomtemperature and slurried in hexane (100 mL), filtered and washed withhexane to give 7.67 g (98% yield) of a 1:1 mixture of the E and Zisomers of ethyl 2-cyano-3-(3-iodophenylamino)acrylate as a white solid,mp 140-141° C.;

¹H NMR (DMSO-d₆) δ 1.25 (t, J=7 Hz, 1.5H), 1.25 (t, J=7 Hz, 1.5H), 4.18(q, J=7 Hz, 1H), 4.22 (q, J=7 Hz, 1H), 7.15 (t, J=8 Hz, 0.5H), 7.16 (t,J=8 Hz, 0.5H), 7.44 (dd, J=8, 2 Hz, 0.5H), 7.48 (dd, J=8, 2 Hz, 0.5H),7.51 (d, J=8 Hz, 0.5H), 7.52 (d, J=8 Hz, 0.5H), 7.81 (t, J=2 Hz, 0.5H),7.96 (t, J=2 Hz, 0.5H), 8.31 (d, J=14 Hz, 0.5H), 8.48 (d, J=14 Hz,0.5H), 10.65 (d, J=14 Hz, 0.5H), 10.75 (d, J=14 Hz, 0.5H); MS (ES) m/z341.3 (M−1). Analysis for C₁₂H₁₁IN₂O₂: Calcd: C, 42.13; H, 3.24; N,8.19. Found: C, 42.08; H, 3.34; N, 7.93.

REFERENCE EXAMPLE 12 4-Chloro-7-iodo-3-quinolinecarbonitrile

A mixture of ethyl 2-cyano-3-(3-iodophenylamino)acrylate (E/Z 1:1) (5.0g, 14.61 mmol) in a 3 to 1 mixture of diphenyl ether and biphenyl (150mL) was heated at reflux for 4 hours. After cooling to room temperature,the reaction mixture was poured into hexane (1.0 L). The precipitatedsolids were collected by filtration and thoroughly washed with hexane togive 3.60 g of crude 7-iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile asa light brown solid.

A mixture of crude 7-iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (2.2g, 7.43 mmol) and phosphorous oxychloride (14 mL) was heated at refluxfor 45 minutes, then cooled to room temperature. The resultant mixturewas evaporated to remove excess phosphorous oxychloride. The residue wasslurried in aqueous saturated bicarbonate and water (1:1) (200 mL) andextracted with ethyl acetate. The combined extracts were dried oversodium sulfate, concentrated on silica gel (5 g) and purified by flashsilica gel chromatography, eluting with ethyl acetate/hexane (1:10), togive 1.40 g (60% yield) of 4-chloro-7-iodo-3-quinolinecarbonitrile as awhite solid, mp 165-167° C.;

¹H NMR (DMSO-d₆) δ 8.07 (d, J=9 Hz, 1H), 8.20 (dd, J=9 Hz, 1H), 8.64 (d,J=2 Hz, 1H), 9.20 (s, 1H); MS (ES) m/z 315.1 (M+1). Analysis forC₁₀H₄ClIN₂: Calcd: C, 38.19; H, 1.28; N, 8.91. Found: C, 38.24; H, 1.44;N, 8.65.

REFERENCE EXAMPLE 134-(2,4-Dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile

A mixture of 4-chloro-7-iodo-3-quinolinecarbonitrile (1.0 g, 3.18 mmol),2,4-dichloro-5-methoxyaniline (prepared by the procedure described in WO8501939-A1) (746 mg, 3.82 mmol) and pyridine hydrochloride (441 mg, 3.82mmol) in 2-ethoxyethanol (16 mL) was heated at 100-110° C. for 2 hours.The resultant mixture was cooled to room temperature and diluted withwater (50 mL) and aqueous saturated sodium bicarbonate (50 mL). Theprecipitated solids were collected by filtration, washed with aqueoussaturated sodium bicarbonate and water and dried to give 1.42 g (94%yield) of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile as alight yellow solid, mp 243-245° C.;

¹H NMR (DMSO-d₆) δ 3.86 (s, 3H), 6.44 (s, 1H), 7.81 (s, 1H), 8.15 (dd,J=9, 2 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 8.40 (d, J=9 Hz, 1H), 8.90 (s,1H); MS (ES) m/z 470.1 (M+1). Analysis for C₁₂H₁₀Cl₂IN₃O-0.65H₂O: Calcd:C, 42.38; H, 2.36; N, 8.72. Found: C, 42.01; H, 2.09; N, 8.75.

REFERENCE EXAMPLE 147-Bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile

Following the procedure for Reference Example 7, a reaction mixture of350 mg (1.3 mmol) of 7-bromo-4-chloro-3-quinolinecarbonitrile 376 mg(1.57 mmol) of 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]benzenamine(prepared by the procedure described in U.S. Pat. No. 4,973,599) and 151mg (1.31 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanolwas heated at 110-120° C. for 1 hour to yield 402 mg of7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrileas a bright yellow solid, mp 258-261° C.;

¹H NMR (DMSO-d₆) δ 8.84 (s, 1H), 8.51 (d, J=9 Hz, 1H), 8.22 (d, J=2 Hz,1H), 7.91 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H), 7.75 (d, J=2 Hz, 1H),7.60 (d, J=1.8 Hz, 1H); 7.30 (dd, J=8, 2 Hz, 1H), 7.18 (d, J=8 Hz, 1H),3.77 (s, 3H); MS (ES) m/z 469.9, 471.9 (M+1). Analysis forC₂₀H₁₃BrClN₅S-1.8HCl: Calcd: C, 44.78; H, 2.78; N, 13.06. Found: C,44.74; H, 2.78; N, 13.12.

REFERENCE EXAMPLE 15 Methyl 5-Methoxy-2-nitro-4-(benzyloxy)benzoate

Nitric acid (27 mL of a 70% solution) was added dropwise to a suspensionof methyl 3-methoxy-4-(benzyloxy)benzoate (14.5 g, 53.0 mmol) in 150 mLof acetic acid. The mixture was stirred at room temperature for 15minutes and then was heated at 50° C. for 4 hours. The reaction wascooled to room temperature and poured into ice. The precipitate wascollected by filtration, washed with water and dried to provide 16.4 gof methyl 5-methoxy-2-nitro-4-(benzyloxy)benzoate as an off-white solid,mp 104-105° C.;

MS (ES) m/z 318.1 (M+1). Analysis for C₁₆H₁₅NO₆: Calcd: C, 60.57; H,4.76; N, 4.41. Found: C, 60.39; H, 4.70; N, 4.28.

REFERENCE EXAMPLE 16 Methyl 4-Hydroxy-5-methoxy-2-nitrobenzoate

To a −78° C. solution of methyl 5-methoxy-2-nitro-4-(benzyloxy)benzoate(5 g, 15.6 mmol) in 100 mL of dichloromethane was added dropwise asolution of boron trichloride (46 mL of a 1M solution in methylenechloride, 46 mmol). After 5 minutes, 130 mL of methanol was added andthe solution was allowed to warm to room temperature. The solvents wereremoved in vacuo and the residue was partitioned between methylenechloride and saturated aqueous sodium bicarbonate. The aqueous layer wasextracted with additional methylene chloride and the organic layers werecombined and dried over sodium sulfate. The solution was passed througha plug of hydrous magnesium silicate, concentrated in vacuo and dried toprovide 3.5 g (97%) of methyl 4-hydroxy-3-methoxy-6-nitrobenzoate as ayellow solid, mp 101-102° C.;

MS (ES) m/z 226.1 (M+1). Analysis for C₉H₉NO₆: Calcd: C: 47.58; H: 3.99;N: 6.17. Found: C: 47.60; H: 3.94; N: 6.14.

REFERENCE EXAMPLE 17 Methyl5-Methoxy-2-nitro-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate

To a solution of methyl 4-hydroxy-3-methoxy-6-nitrobenzoate (1.0 g, 4.4mmol) in a mixture of 10 mL of methylene chloride and 1 mL of pyridine,trifluoromethanesulfonic anhydride (0.73 mL, 6.6 mmol) was addeddropwise. The reaction mixture was stirred at room temperature for 2hours, then washed sequentially with 2N hydrochloric acid, water andsaturated sodium bicarbonate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was dried toprovide 1.4 g of methyl5-methoxy-2-nitro-4-{[(trifluoromethyl)sulfonyl]oxy}-benzoate as a tansolid, mp 69-70° C.;

MS (ES) m/z 360.1 (M+1). Analysis for C₁₀H₈F₃NO₈S: Calcd: C, 33.43; H,2.24; N, 3.90. Found: C, 33.66; H, 2.20; N, 3.83.

REFERENCE EXAMPLE 18 Methyl2-Amino-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate

A mixture of methyl5-methoxy-2-nitro-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (1.50 g,4.1 mmol), ammonium chloride (2.17 g, 41 mmol) and iron (1.17 g, 21mmol) in 30 mL of ethanol and 10 mL of water was heated at reflux forseveral hours. The reaction was cooled to room temperature and theethanol was removed in vacuo. Sodium bicarbonate was added to theresidue and the mixture was extracted with ethyl acetate. The organiclayer was washed with water followed by saturated sodium bicarbonate.The organic layer was then dried over sodium sulfate and passed througha plug of hydrous magnesium silicate to provide 1.49 g of methyl2-amino-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate asoff-white solid,

mp 85-87° C.; MS (ES) m/z 330.1 (M+1). Analysis for C₁₀H10F₃NO₆S: Calcd:C, 36.48; H, 3.06; N, 4.25. Found: C, 36.66; H, 3.09; N, 4.22.

REFERENCE EXAMPLE 19 Methyl2-{[(E)-(Dimethylamino)methylidene]amino}-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate

A solution of methyl2-amino-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (9.5 g,28.8 mmol) and 25 mL of dimethylformamide dimethylacetal was heated at110° C. for several hours then cooled to room temperature and dilutedwith toluene. The mixture was concentrated in vacuo to give 10.2 g ofmethyl2-{[(E)-(dimethylamino)methylidene]amino}-5-methoxy-4{[(trifluoromethyl)sulfonyl]oxy}benzoateas a thick oil;

MS (ES) m/z 385.1 (M+1). Analysis for C₁₃H₁₅F₃N₂O₆S: Calcd: C, 40.63; H,3.93; N, 7.29. Found: C, 40.48; H, 3.86; N, 6.99.

REFERENCE EXAMPLE 20 3-Cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinylTrifluoromethanesulfonate

To a solution of n-butyl lithium (25 mL of a 2.5M solution in hexane,62.5 mmol) in 50 mL of tetrahydrofuran was added a solution ofacetonitrile (5.0 mL, 95.7 mmol) in 80 mL of tetrahydrofuran. Thereaction mixture was stirred at −78° C. for 15 minutes. A solution ofmethyl2-{[(E)-(dimethylamino)methylidene]amino}-5-methoxy-4{[(trifluoromethyl)sulfonyl]oxy}benzoate(8.0 g 20.8 mmol) in 20 mL of tetrahydrofuran was added and stirring wascontinued for 2 hours at −78° C. The reaction was quenched by theaddition of 15 mL of acetic acid and the mixture was allowed to warm toroom temperature. The volatiles were removed in vacuo and water wasadded to the residue. The white precipitate was collected and purifiedby flash silica gel chromatography eluting with 10% hexane in ethylacetate to provide 5.0 g of3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyltrifluoromenthanesulfonate as a yellow solid, mp>240° C. (dec);

MS (ES) m/z 349.5 (M+1). Analysis for C₁₂H₇F₃N₂O₅S-0.13H₂O: Calcd: C,41.09; H, 2.09; N, 7.97. Found: C, 40.97; H, 2.18; N, 7.58.

REFERENCE EXAMPLE 21 4-Chloro-3-cyano-6-methoxy-7-quinolinylTrifluoromethanesulfonate

To a solution of 3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyltrifluoromethanesulfonate (5.0 g, 14 mmol) in oxalyl chloride (30 mL ofa 2M solution in dichloromethane) was slowly added 1 mL ofdimethylformamide. The reaction mixture was heated at 40° C. for 3 hthen cooled to room temperature and concentrated in vacuo. The residuewas added to crushed ice and the resulting precipitate was collected andwashed with water. The solid was dissolved in methylene chloride, driedover sodium sulfate and passed through a plug of hydrous magnesiumsilicate. The filtrate was concentrated in vacuo to provide 3.2 g (62%)of 4-chloro-3-cyano-6-methoxy-7-quinolinyl trifluoromethanesulfonate asan off-white solid, mp 112-113° C.;

MS (ES) m/z 367.0 (M+1). Analysis for C₁₂H₆ClF₃N₂O₄S-0.24H₂O: Calcd: C,38.83; H, 1.76; N, 7.51; Found: C, 38.84; H, 1.76; N, 7.51.

REFERENCE EXAMPLE 223-Cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinylTrifluoromethanesulfonate

A mixture of 4-chloro-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (200 mg, 0.54 mmol),2,4-dichloro-5-methoxyaniline (114 mg, 0.59 mmol) prepared by theprocedure described in WO 8501939-A1 and pyridine hydrochloride (62 mg,0.54 mmol) in 5 mL of ethoxyethanol was heated at 110° C. for 2 hoursthen cooled to room temperature and partitioned between saturated sodiumbicarbonate and ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash silica gel chromatography eluting with 3:2 ethyl acetate:hexane toprovide 254 mg of3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate as an off-white solid, mp 220-223° C.;

MS (ES) m/z 523.9 (M+1). Analysis for C₁₉H₁₂Cl₂F₃N₃O₅S: Calcd: C, 43.69;H, 2.32; N, 8.05. Found: C, 43.87; H, 2.34; N, 7.91.

REFERENCE EXAMPLE 23 1-[(4-Bromo-2-thienyl)methyl]-4-ethylpiperazine

Sodium cyanoborohydride (1.07 g, 17.01 mmol) was added to a mixture of4-bromo-2-thiophenecarboxaldehyde (2.50 g, 13.08 mmol),N-ethylpiperazine (1.49 g, 13.08 mmol) and acetic acid (942 mg, 15.70mmol) in 6 mL of ethanol and the mixture was stirred at room temperaturefor 4 hours, then poured into saturated sodium bicarbonate and extractedwith methylene chloride. The organic layer was extracted with 10%aqueous hydrochloric acid and the aqueous layer was neutralized with 10Nsodium hydroxide and saturated sodium bicarbonate. The aqueous layer wasextracted with methylene chloride and the combined methylene chlorideextracts were dried over magnesium sulfate, filtered and concentrated invacuo. The residue was recrystallized from hexane to provide 170 mg of alight yellow solid. Concentration of the mother liquor provided anadditional 2.02 g of 1-[(4-bromo-2-thienyl)methyl]-4-ethylpiperazine, mp168-169° C.;

¹H NMR (DMSO-d₆) δ 1.22 (t, J=7 Hz, 3H), 2.75-3.55 (m, 10H), 3.77 (s,2H), 7.05 (s, 1H), 7.61 (s, 1H); MS (ES) m/z 289.2 (M+1).

REFERENCE EXAMPLE 244-{[2-(4-Morpholinylmethyl)-3-thienyl]methyl}morpholine

Using an analogous procedure to that described for Reference Example 23,4-{[2-(4-morpholinylmethyl)-3-thienyl]methyl}morpholine was preparedfrom 2,3-bisthiophene-carboxaldehyde and morpholine in 34% yield as awhite solid, mp 58-60° C.;

¹H NMR (DMSO-d₆) δ 2.25-2.35 (m, 4H), 2.41 (t, J=4 Hz, 4H), 3.42 (s,2H), 3.53-3.58 (m, 8H), 3.65 (s, 2H), 6.92 (d, J=5 Hz, 1H), 7.34 (d, J=5Hz, 1H); MS (ES) m/z 283.2 (M+1); Calcd: C, 59.54; H, 7.85; N, 9.92.Found: C, 59.26; H, 3.90; N, 10.14.

REFERENCE EXAMPLE 25 4-[(5-Bromo-2-thienyl)methyl]morpholine

Using an analogous procedure to that described for Reference Example 23,4[(5-bromo-2-thienyl)methyl]morpholine was prepared from5-bromo-2-carboxaldehyde and morpholine in 40% yield as a semi-solid;

¹H NMR (DMSO-d₆) δ 2.90-3.10 (m, 2H), 3.20-3.35 (m, 2H), 3.60-3.75 (m,2H), 3.85-4.00 (m, 2H), 4.35 (s, 2H), 7.10-7.30 (m, 2H); MS (ES) m/z289.1 (M+1)

REFERENCE EXAMPLE 26 4-(5-Hexenyl)morpholine

A mixture of 6-bromohexene (2.0 g, 12.27 mmol), morpholine (2.15 g,24.66 mmol) and a catalytic amount of sodium iodide in ethylene glycoldimethyl ether was heated at 80° C. for 1 hour to give a thick solidcake which was cooled to room temperature and slurried with hexane. Thesuspension was filtered and washed with hexane and diethyl ether. Thefiltrate was concentrated and dried in vacuo to give 1.75 g (84% yield)of 4-(5-hexenyl)morpholine as a colorless oil;

¹H NMR (DMSO-d₆) δ 1.35-1.60 (m, 4H), 2.06 (dt, J=17, 7 Hz, 2H), 2.33(t, J=7 Hz, 2H), 2.44 (t, J=5 Hz, 4H), 3.72 (t, J=5 Hz, 4H), 4.93-5.03(m, 1H), 5.74-5.87 (m, 2H); MS (ES) m/z 170.1 (M+1).

REFERENCE EXAMPLE 27 4-[(E)-3-(3-Thienyl)-2-propenoyl]morpholine

A mixture of 3-(2-thienyl)acrylic acid (2.0 g, 12.97 mmol), morpholine(2.37 g, 27.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (2.43 g, 14.27 mmol) and a catalytic amount of4-dimethylaminopyridine in methylene chloride (70 mL) was stirred atroom temperature for 2 hours and diluted with methylene chloride to avolume of 150 ml. The resultant mixture was washed with 5% hydrochloricacid (50 mL×2), saturated aqueous sodium bicarbonate (50 mL), and water(50 mL) and concentrated. The residue was slurried in hexane, filteredand washed with hexane to give 1.78 g of4-[(E)-3-(3-thienyl)-2-propenoyl]morpholine as is a white solid, mp141-142° C.;

¹H NMR (DMSO-d₆) δ 3.60-3.80 (m, 8H), 6.64 (d, J=15 Hz, 1H), 7.04 (dd,J=5, 4 Hz, 1H), 7.23 (d, J=4 Hz, 1H), 7.32 (d, J=5 Hz, 1H), 7.84 (d,J=15 Hz, 1H); MS (ES) m/z 224.1 (M+1).

REFERENCE EXAMPLE 28 4-[(E)-3-(2-Thienyl)-2-propenyl]morpholine

Lithium aluminum hydride (10M in tetrahydrofuran, 8.96 mL, 8.96 mmol)was added to a stirring mixture of4-[(E)-3-(3-thienyl)-2-propenoyl]morpholine (1.0 g, 4.48 mmol) andtetrahydrofuran (22 mL) at room temperature. The mixture was heated to45° C. for 2 hours. Ten percent hydrochloric acid (3.7 mL) was addeddropwise to destroy the excess lithium aluminum hydride. The resultantmixture was diluted with 20 mL of water and 10 ml of 1N sodium hydroxideand extracted with methylene chloride (940 mL×4). The combined organiclayers were washed with saturated sodium chloride and water, dried oversodium sulfate and concentrated to give a light yellow syrup which waspurified by flash silica gel column chromatography, eluting with 1%methanol in methylene chloride) to give 450 mg (48%) of4-[(E)-3-(2-thienyl)-2-propenyl]morpholine as a colorless oil;

¹H NMR (DMSO-d₆) δ 2.52 (t, J=5 Hz, 4H), 3.13 (d, J=7 Hz, 2H), 3.75 (t,J=5 Hz, 4H), 6.09 (dt, J=16, 7 Hz, 1H), 6.66 (d, J=16 Hz, 1H), 6.83-6.97(m, 2H), 7.14 (dd, J=5, 1 Hz, 1H); MS (ES) m/z 209.9 (M+1).

REFERENCE EXAMPLE 29 4-[4-(2-Thienyl)butyl]morpholine

Using an analogous procedure to that described for Reference Example 27,4-[4-(2-thienyl)butanoyl]morpholine was prepared from4-(2-thienyl)butyric acid and morpholine in 71% yield as a colorlessoil;

¹H NMR (CDCl₃): δ 1.99-2.08 (m, 2H), 2.35 (t, J=7 Hz, 2H), 2.91 (t, J=7Hz), 2H), 3.40 (t, J=5 Hz, 2H), 3.55-3.70 (m, 6H), 6.80 (dd, J=3, 1 Hz,6.92 (dd, J=5, 3 Hz, 1H), 7.12 (dd, J=5, 1 Hz, 1H); MS (ES) m/z 239.9(M+1). Analysis for C₁₂H₁₇NO₂S-0.2H₂O: Calcd: C, 59.32; H, 7.20; N,5.77. Found: C, 59.38; H, 6.96; N, 5.64.

REFERENCE EXAMPLE 30 4-[4-(2-Thienyl)butyl]morpholine

Using an analogous procedure to that described for Reference Example 28,4-[4-(2-thienyl)butyl]morpholine was prepared from reduction of4-[4-(2-thienyl)butanoyl]morpholine with lithium aluminum hydride in 86%yield as a colorless oil;

¹H NMR (DMSO-d₆) δ 1.40-1.55 (m, 2H), 1.56-1.68 (m, 2H), 2.20-2.35 (m,4H), 2.82 (t, J=10 Hz, 2H), 3.27-3.40 (m, 4H), 3.55 (t, J=5 Hz, 2H),6.83 (dd, J=3, 1 Hz, 1H), 6.92 (dd, J=5, 3 Hz, 1H), 7.31 (dd, J=5, 1 Hz,1H); MS (ES) m/z 226.2 (M+1).

REFERENCE EXAMPLE 31 4-(3-Bromobenzyl)morpholine

To a mixture of 5.0 g (27.0 mmol) of 3-bromobenzaldehyde, 2.35 (27.0mmol) of morpholine and 1.95 g (32.4 mmol) of acetic acid in 100 mL ofethanol was added 2.21 g (35.1 mmol) of sodium cyanoborohydride inportions over 5 minutes. The resulting mixture was stirred at roomtemperature for 15 hours. After removal of ethanol in vacuo, the residuewas partitioned between 40 mL of methylene chloride and 40 mL ofsaturated aqueous sodium bicarbonate solution. The layers wereseparated, and the aqueous layer was extracted with 2×20 mL methylenechloride. The organic layers were combined and extracted with 3×50 mL ofa 1N hydrochloric acid solution. The combined aqueous solution wasneutralized with 5N sodium hydroxide, then sodium bicarbonate. The milkyaqueous solution was extracted with 3×50 mL methylene chloride, and thecombined organic layers were dried over magnesium sulfate. Followingremoval of the magnesium sulfate by filtration, and removal of methylenechloride in vacuo, 3.5 g of 4-(3-bromobenzyl)morpholine was obtained asa clear oil;

¹H NMR (DMSO-d₆) δ 7.50 (d, J=1 Hz, 1H), 7.47-7.43 (m, 1H), 7.33-7.26(m, 2H), 3.57 (t, J=5 Hz, 4H), 3.46 (s, 2H), 2.34 (t, J=5 Hz, 4H); MS(ES) m/z 256.2, 258.1 (M+1). Analysis for C₁₁H₁₄BrNO: Calcd: C, 51.58;H, 5.51; N, 5.47. Found: C, 51.62; H, 5.27; N, 5.31.

REFERENCE EXAMPLE 32 1-Ethyl-4-[2-(4-iodophenyl)acetyl]piperazine

A mixture of 4.00 g (15.3 mmol) of 4-iodophenylacetic acid, 1.74 g (15.3mmol) of ethylpiperazine, 3.22 g (16.8 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.01 g(0.082 mmol) of 4-(dimethylamino)-pyridine in 35 mL of methylenechloride was stirred at room temperature for 15 hours. The mixture waswashed with 30 mL water, then extracted with 3×30 mL 1N hydrochloricacid. The combined aqueous layers were neutralized with 10N sodiumhydroxide, then potassium bicarbonate. The milky solution was extractedwith 3×40 mL of ethyl acetate, and the combined organic layers weredried over magnesium sulfate. After filtering off the magnesium sulfate,the solvent was removed in vacuo to provide 3.6 g of1-ethyl-4-[2-(4-iodophenyl)acetyl]piperazine as a white solid, mp 81-83°C.;

¹H NMR (DMSO-d₆) δ 7.65 (d, J=8 Hz, 2H), 7.03 (d, J=8 Hz, 2H), 3.66 (s,2H), 3.44 (m, 4H), 2.34-2.27 (m, 6H), 0.98 (t, J=7 Hz, 3H); MS (ES) m/z359.1 (M+1). Analysis for C₁₄H₁₉IN₂C: Calcd: C, 46.94; H, 5.35; N, 7.82.Found: C, 46.85; H, 5.37; N, 7.83.

REFERENCE EXAMPLE 33 1-Ethyl-4-[2-(4-iodophenyl)ethyl]piperazine

To a solution of 3.52 g (9.83 mmol) of1-ethyl-4-[2-(4-iodophenyl)acetyl]piperazine (Reference Example 32) in30 mL of tetrahydrofuran was added 1.86 mL (19.7 mmol) of borane-methylsulfide at room temperature while stirring. The reaction mixture washeated at reflux for 2 hours. After cooling, the mixture was quenchedwith methanol, followed by removal of the solvents in vacuo. The residuewas taken up in 10 mL ethanol and 20 mL 1N sodium hydroxide. Thereaction mixture was heated at reflux for 2 hours, then cooled to roomtemperature. The mixture was partitioned between 75 mL of ethyl acetateand 40 mL of water. Following separation of the layers, the aqueouslayer was further extracted with 2×30 mL of ethyl acetate. The organiclayers were combined, washed with saturated sodium chloride and thendried over magnesium sulfate. After filtering off the magnesium sulfate,the solvent was removed in vacuo to provide the crude product. Thismaterial was purified by passing through a short pad of silica gel,eluting with 95:5 methylene chloride/methanol, to provide 3.2 g of1-ethyl-4-[2-(4-iodophenyl)ethyl]piperazine as a white wax;

¹H NMR (DMSO-d₆) δ 7.61 (d, J=8 Hz, 2H), 7.04 (d, J=8 Hz, 2H), 2.67 (t,J=7 Hz, 2H), 2.48-2.27 (m, 10H), 2.27 (t, J=7 Hz, 2H), 0.97 (t, J=7 Hz,3H); MS (ES) m/z 345.1 (M+1). Analysis for C₁₄H₂₁IN₂.0.17CH₂Cl₂: Calcd:C, 47.45; H, 6.00; N, 7.81. Found: C, 47.83; H, 5.68; N, 7.43.

REFERENCE EXAMPLE 34 1-(4-Bromobenzyl)-4-ethylpiperazine

Using an analogous procedure to that described for Reference Example 31,5.0 g (27.0 mmol) of 4-bromobenzaldehyde, 3.09 g (27.0 mmol) of ethylpiperazine, 1.95 g (32.4 mmol) of acetic acid and 2.21 g (35.1 mmol) ofsodium cyanoborohydride in 100 mL of ethanol were allowed to react atroom temperature. Workup provided 4.2 g of1-(4-bromobenzyl)-4-ethylpiperazine as a yellow oil;

¹H NMR (DMSO-d₆) δ 7.50 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 3.41 (s,2H), 2.36-2.30 (m, 8H), 2.29 (q, J=7 Hz, 2H), 0.97 (t, J=7 Hz, 3H); MS(ES) m/z 283.1, 285.1 (M+1). Analysis for C_(13H) ₁₉BrN₂.0.3H₂O: Calcd:C, 54.10; H, 6.85; N, 9.71. Found: C, 54.25; H, 6.76; N, 9.71.

REFERENCE EXAMPLE 35 4-[2-(3-Bromophenyl)ethyl]morpholine

Using an analogous procedure to that described for Reference Example 33,a solution of 3.0 g (10.6 mmol) of 4-[(3-bromophenyl)acetyl]morpholine(prepared according to the procedure of WO 9842670) in 25 mL of drytetrahydrofuran was allowed to react with 2.0 mL (21.1 mmol) ofborane-methyl sulfide. Following the same workup and treatment withaqueous sodium hydroxide, 2.1 g of 4-[2-(3-bromophenyl)ethyl]morpholinewas obtained as a clear oil;

¹H NMR (DMSO-d₆) δ 7.45 (d, J=1 Hz, 1H), 7.39-7.34 (m, 1H), 7.26-7.23(m, 2H), 3.56 (t, J=5 Hz, 4H), 2.73 (t, J=7 Hz, 2H), 2.52-2.49 (m, 2H),2.41 (t, J=5 Hz, 4H); MS (ES) m/z 270.2, 272.1 (M+1). Analysis forC₁₂H₁₆BrNO: Calcd: C, 53.35; H, 5.97; N, 5.18. Found: C, 53.16; H, 6.07;N, 5.46.

REFERENCE EXAMPLE 364-[4-Bromo-2-(4-morpholinylcarbonyl)benzoyl]morpholine

A mixture of 3.00 g (12.2 mmol) of 4-bromophthalic acid, 2.13 g (24.4mmol) of morpholine, 5.16 g (26.9 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.01 g(0.082 mmol) of 4-(dimethylamino)pyridine in 30 mL of methylene chloridewas stirred at room temperature for 15 hours. The mixture was washedwith 30 mL of water, 2×20 mL of 1N hydrochloric acid and then with 2×20mL of saturated sodium bicarbonate. After filtering off the magnesiumsulfate, the solvent was removed in vacuo. The crude product waspurified by flash silica gel chromatography, eluting with 97:3 methylenechloride/methanol to provide 3.5 g of4-[4-bromo-2-(4-morpholinylcarbonyl)benzoyl]morpholine as a white foam;

¹H NMR (acetone-d₆) δ 7.68 (dd, J=8, 2 Hz, 1H), 7.58 (d, J=2 Hz, 1H),7.35 (d, J=8 Hz, 1H), 3.65 (br s, 12H), 3.29 (br s, 4H); MS (ES) m/z383.3, 385.2 (M+1). Analysis for C₁₆H₁₉BrN₂O₄: Calcd: C, 50.14; H, 5.00;N, 7.31. Found: C, 49.98; H, 4.76; N, 7.20.

REFERENCE EXAMPLE 37 4-[4-Bromo-2-(4-morpholinymethyl)benzyl]morpholine

Using an analogous procedure to that described for Reference Example 33,a solution of 2.10 g (5.48 mmol) of4-[4-bromo-2-(4-morpholinylcarbonyl)benzoyl]morpholine in 25 mL oftetrahydrofuran was reacted with 2.10 mL (21.9 mmol) of borane-methylsulfide. Following the same workup and treatment with aqueous sodiumhydroxide, 1.6 g of 4-[4-bromo-2-(4-morpholinylmethyl)benzyl]morpholinewas obtained as a clear oil;

¹H NMR (DMSO-d₆) δ 7.50 (d, J=2 Hz, 1H), 7.41 (dd, J=8, 2 Hz, 1H), 7.26(d, J=8 Hz, 1H), 3.57-3.52 (m, 12H), 2.36-2.32 (m, 8H); MS (ES) m/z355.3, 357.4 (M+1). Analysis for C₁₆H₂₃BrN₂O₂.0.15CH₂Cl₂: Calcd: C,52.71; H, 6.38; N, 7.61. Found: C, 52.73; H, 6.11; N, 7.33.

REFERENCE EXAMPLE 38 4-[2-(4-Iodophenyl)acetyl]morpholine

Using an analogous procedure to that described for Reference Example 36,a mixture of 4.0 g (15.3 mmol) of 4-iodoacetic acid, 1.33 g (15.3 mmol)of morpholine, 3.22 g (16.8 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.01 g(0.082 mmol) of 4-(dimethylamino)pyridine in 35 mL of methylene chloridewas reacted at room temperature. Workup provided 4.2 g of4-[2-(4-iodophenyl)acetyl]morpholine as a white solid, mp 114-117° C.;

¹H NMR (DMSO-d₆) δ 7.66 (d, J=8 Hz, 2H), 7.03 (d, J=8 Hz, 2H), 3.68 (s,2H), 3.54-3.42 (m, 8H); MS (ES) m/z 332.2 (M+1). Analysis forC₁₂H₁₄INO₂: Calcd: C, 43.52; H, 4.26; N, 4.23. Found: C, 43.74; H, 4.29;N, 4.43.

REFERENCE EXAMPLE 39 4-[2-(4-Iodophenyl)ethyl]morpholine

Using an analogous procedure to that described for Reference Example 33,a solution of 3.50 g (5.48 mmol) of 4-[2-(4-iodophenyl)acetyl]morpholinein 35 mL of tetrahydrofuran was reacted with 2.01 mL (21.1 mmol) ofborane-methyl sulfide. Following the same workup and treatment withaqueous sodium hydroxide, 3.0 g of 4-[2-(4-iodophenyl)ethyl]morpholinewas obtained as a white solid, mp 64-67° C.;

¹H NMR (DMSO-d₆) δ 7.62 (d, J=8 Hz, 2H), 7.06 (d, J=8 Hz, 2H), 3.55 (t,J=5 Hz, 4H), 2.69 (t, J=7 Hz, 2H), 2.47 (t, J=7 Hz, 2H), 2.39 (t, J=5Hz, 4H); MS (ES) m/z 318.0 (M+1). Analysis for C₁₂H₁₆INO: Calcd: C,45.44; H, 5.08; N, 4.42. Found: C, 45.58; H, 5.09; N, 4.56.

REFERENCE EXAMPLE 40 4-(4-Pentenyl)morpholine

Using an analogous procedure to that described for Reference Example 26,4-(4-pentenyl)morpholine was prepared from 5-bromopentene and morpholinein 40% yield as colorless oil;

¹H NMR (DMSO-d₆), δ 1.54-1.61 (m, 2H), 2.07 (dt, J=8, 7 Hz, 2H), 2.34(t, J=8 Hz, 2H), 2.44 (t, J=5 Hz, 4H), 3.72 (t, J=5 Hz, 4H), 4.90-5.06(m, 2H), 5.75-5.88 (m, 1H); MS (ES) m/z 155.9 (M+1).

REFERENCE EXAMPLE 41 4-(4-Pentynyl)morpholine

Using an analogous procedure to that described for Reference Example 26,4-(4-pentynyl)morpholine was prepared from 5-chloropentyne andmorpholine in 31% yield as colorless oil;

¹H NMR (DMSO-d₆), δ 1.66-1.76 (m, 2H), 1.95 (t, J=3 Hz, 1H), 2.26 (dt,J=7, 3 Hz, 2H), 2.36-2.49 (m, 6H), 3.72 (t, J=5 Hz, 4H); MS (ES) m/z153.9 (M+1).

REFERENCE EXAMPLE 42 4-[(5-Bromo-2-furanyl)methyl]morpholine

Using an analogous procedure to that described for Reference Example 23,4-[(5-bromo-2-furanyl)methyl]morpholine was prepared from5-bromo-2-furaldehyde and morpholine in 54% yield as a colorless oil;

¹H NMR (DMSO-d₆): δ 2.36 (t, J=5 Hz, 4H), 3.46 (s, 2H), 3.56 (t, J=5 Hz,4H) 6.37 (d, J=3 Hz, 1H), 6.49 (d, J=3 Hz, 1H); MS (ES) m/z 248.1 (M+1).

REFERENCE EXAMPLE 43 Tributyl[5-(1,3-dioxolan-2-yl)-3-thienyl]stannane

To a −78° C. solution of 2-(4-bromo-2-thienyl)-1,3-dioxolane (4.41 g,18.76 mmol) (prepared according to the procedure of Johnson, A., J. Org.Chem., 41, 1320 (1976) in 20 mL of tetrahydrofuran was addedtri-n-butylstannyl chloride (6.0 mL, 22.15 mmol) followed by 2.5Mn-butyl lithium in hexane (10.0 mL, 25.0 mmol). The reaction mixture wasstirred at −78° C. for 3.5 hours then partitioned between ethyl acetateand water. The organic layer was washed with water, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash silica gel chromatography eluting with 8:1 hexane:ethyl acetate toprovide 4.86 g of tributyl[5-(1,3-dioxolan-2-yl)-3-thienyl]stannane (58%yield) as a colorless oil;

¹H NMR (DMSO-d₆): δ 0.85 (t, J=6 Hz, 9H), 1.02 (dd, J=6 Hz, 6H), 1.28(m, 6H), 1.50 (m, 6H), 3.88-4.07 (m, 4H), 6.06 (s, 1H), 7.20 (s, 1H),7.50 (s, 1H); MS (ES) m/z 447.1 (M+1).

REFERENCE EXAMPLE 44 4-[(5-Bromo-3-pyridinyl)carbonyl]morpholine

A mixture of 5-bromonicotinic acid (5.05 g, 25 mmol) andcarbonyldiimidazole (4.86 g, 30 mmol) in 100 mL of tetrahydrofuran wasstirred at room temperature for two hours. Morpholine (5.0 g, 57.4 mmol)was added to the solution, and the mixture was stirred for oneadditional hour at room temperature. The mixture was partitioned betweenethyl acetate and water. The ethyl acetate layer was washed with waterand brine, dried over magnesium sulfate, and filtered through hydrousmagnesium silicate. Concentration of the filtrate provided 2.73 g (40%yield) of 4-[(5-bromo-3-pyridinyl)carbonyl]morpholine as a white solid,mp 49-51° C.;

¹H NMR (DMSO-d₆) δ 3.32 (m, 4H), 3.63 (m, 4H), 8.15 (t, J=2 Hz, 1H),8.61 (d, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H); MS (E) m/z 271.2 (M+1).Analysis for C₁₀H₁₁BrN₂O₂; Calcd: C, 44.30; H, 4.09; N, 10.33. Found: C,43.91; H, 3.99; N, 10.35.

REFERENCE EXAMPLE 45 4-[(5-Bromo-3-pyridinyl)methyl]morpholine

To a solution of 4-[(5-bromo-3-pyridinyl)carbonyl]morpholine (2.71 g, 10mmol) in 100 mL of tetrahydrofuran was added 10 mL of 10 M borane-methylsulfide complex (100 mmol). The mixture was stirred at room temperaturefor 20 hours, and quenched slowly with 100 mL of 1 N sodium hydroxide.The resulting mixture was stirred at room temperature for 24 hours.Ethyl acetate was added, and the layers were separated. The ethylacetate layer was dried over magnesium sulfate. Removal of the solventin vacuo gave a residue which was purified by flash silica gelchromatography eluting with a gradient of 2:1 to 1:1 hexane:ethylacetate to provide 1.02 g (40% yield) of4-[(5-bromo-3-pyridinyl)methyl]morpholine as a colorless oil;

¹H NMR (DMSO-d₆) δ 2.36 (t, J=4 Hz, 4H), 3.51 (s, 2H), 3.57 (t, J=4 Hz,4H), 7.97 (t, J=2 Hz, 1H), 8.49 (d, J=2 Hz, 1H), 8.60 (d, J=2 Hz, 1H);MS (ES) m/z 257.2 (M+1). Analysis for C₁₀H₁₃BrN₂O-0.15H₂O; Calcd: C,46.23; H, 5.16; N, 10.78. Found: C, 46.16; H, 5.09; N, 10.53.

REFERENCE EXAMPLE 46 4-(4-Bromobenzyl)morpholine

Using an analogous procedure to that described for Reference Example 31,5.0 g (27.0 mmol) of 3-bromobenzaldehyde, 2.35 g (27.0 mmol) ofmorpholine, 1.95 g (32.4 mmol) of acetic acid and 2.21 g (35.1 mmol) ofsodium cyanoborohydride in 100 mL of ethanol were reacted at roomtemperature. Workup provided 4.5 g of 4-(4-bromobenzyl)morpholine as awhite solid, mp 68-71° C.;

¹H NMR (DMSO-d₆): δ 7.51 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 3.56 (t,J=5 Hz, 4H), 3.43 (s, 2H), 2.33 (t, J=5 Hz, 4H). MS (ES) m/z 256.1,258.1 (M+1). Analysis for C₁₁H₁₄BrNO: Calcd: C, 51.58; H, 5.51; N, 5.47;Found: C, 51.76; H, 5.50; N, 5.35.

REFERENCE EXAMPLE 47 Tributyl[5-(1,3-dioxolan-2-yl)-2-thienyl]stannane

To a −78° C. solution of 2-(2-thienyl)-1,3-dioxolane (4.00 g, 25.64mmol) (prepared according to the procedure of Johnson, A., J. Org.Chem., 41, 1320 (1976) in 30 mL of tetrahydrofuran was added 2.5Mn-butyl lithium in hexane (14.0 mL, 31.0 mmol). The reaction mixture wasstirred at −78° C. for 10 minutes, then stirred at 0° C. for 30 minutes.The reaction mixture was cooled to −78° C. and tri-n-butylstannylchloride (8.4 mL, 31.02 mmol) was added and the reaction mixture wasallowed to warm to room temperature and stirred overnight. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with water, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash silica gelchromatography eluting with 8:1 hexane:ethyl acetate to provide 4.80 gof tributyl[5-(1,3-dioxolan-2-yl)-2-thienyl]stannane (42% yield) as anorange oil;

¹H NMR (DMSO-d₆): δ 0.85 (t, J=6 Hz, 9H), 1.08 (dd, J=6 Hz, 6H), 1.29(m, 6H), 1.51 (m, 6H), 3.87-4.28 (m, 4H), 6.05 (s, 1H), 7.06 (d, J=3 Hz,1H), 7.30 (d, J=3 Hz, 1H); MS (ES) m/z 447.1 (M+1).

REFERENCE EXAMPLE 484-{[6-(Tributylstannyl)-3-pyridinyl])methyl}morpholine

To a −78° C. solution of 2-bromo-5-(morpholinomethyl)pyridine (337.3 mg,1.31 mmol) (prepared according to the procedure of Windscheif P.-M.,Syntheses, 87 (1994) in 2.2 mL of tetrahydrofuran was added 2.5M n-butyllithium in hexane (0.65 mL, 1.62 mmol). The reaction mixture was stirredat −78° C. for 30 minutes where upon a solution of tri-n-butylstannylchloride (434.9 mg, 1.33 mmol) in tetrahydrofuran (0.7 mL ) was added.The resulting reaction mixture was stirred at −78° C. for 4 hours, thenallowed to warm to room temperature. The reaction mixture waspartitioned between diethyl ether and water. The organic layer waswashed with water, dried over sodium sulfate, filtered and concentratedin vacuo, to give 895.7 mg of the crude product as a yellow oil. Ananalytical sample was obtained via purification by preparative thinlayer chromatography, with a developing solvent of 1:1 ethylacetate/hexane, to provide4-{[6-(tributylstannyl)-3-pyridinyl]methyl}morpholine as a yellow oil;

¹H NMR (DMSO-d₆) δ 0.88 (t, J=7 Hz, 9H), 1.12 (dd, J=6 Hz, 6H), 1.34 (m,6H), 1.54 (m, 6H), 2.44 (t, J=5 Hz, 4H), 3.46 (s, 2H), 3.70 (m, 4H),7.36 (d, J=8 Hz, 1H), 7.48 (m, 1H), 8.66 (s, 1H); MS (ES) m/z 469.2(M+1). Analysis for C₂₂H₄₀N₂OSn: Calcd: C, 56.55; H, 8.63; N, 5.99.Found: C, 56.76; H, 8.28; N, 5.83.

REFERENCE EXAMPLE 49 2-(Phenylsulfonyl)ethanamine

An oven dried flask was charged with 2-(phenylsulfonyl)acetonitrile (5.0g, 27.59 mmol) and tetrahydrofuran (2.67 mL) under nitrogen. The mixturewas stirred and heated to reflux. Borane-methyl sulfide complex (3.26mL, 30.35 mmol) was added at a rate that the reaction mixture gentlyrefluxed (caution: gas evolution may be vigorous!). Dimethyl sulfide wasdistilled and collected during the addition. The reaction mixture washeated at reflux for an additional 30 minutes and then cooled to roomtemperature. 6.0N Hydrochloric acid (16.5 mL) was very slowly added tothe solidified reaction mixture followed by heating at reflux for 20minutes to give a clear solution. The reaction mixture was cooled toroom temperature, basified with 10N sodium hydroxide to pH 8-9 andextracted with ethyl acetate. The combined extracts were dried oversodium sulfate, concentrated and purified by flash column chromatographyeluting with 1% methanol in methylene chloride to give 3.25 g (64%yield) of 2-(phenylsulfonyl)ethanamine as a colorless oil;

¹HNMR (DMSO-d₆) δ 2.78 (t, J=7 Hz, 2H), 3.36 (t, J=7 Hz, 2H), 7.69 (t,J=7 Hz, 2H), 7.76 (t, J=7 Hz, 1H), 7.89 (d, J=7 Hz, 2H); MS (ES) m/z186.0 (M+H).

REFERENCE EXAMPLE 50 N-(2-Methoxy-5-nitrophenyl)acetamide

To a stirred solution of 90 g (0.54 mol) of 2-methoxy-5-nitroaniline in1100 mL of water was slowly added acetic acid (200 mL, 2.12 mol) at roomtemperature. The reaction mixture was stirred at room temperature for1.5 hours and filtered. The solid was washed with water, ether, anddried to give 133 g of crude yellow product (90% yield), mp 172-177° C.;

¹H NMR (DMSO-d₆) δ 9.56 (s, 1H), 9.00 (d, J=3 Hz, 1H), 8.02 (dd, J=9 Hz,3 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 3.99 (s, 3H), 2.15 (s, 3H); MS (ES) m/z211.1 (M+1).

REFERENCE EXAMPLE 51 N-(5-Amino-2-methoxyphenyl)acetamide

An amount of 30 g (0.14 mol) of N-(2-methoxy-5-nitrophenyl)acetamide wasdissolved in 750 mL of methanol and 195 mL of water, and to this wasadded 40 g (0.72 mol) of iron powder, and 53 g (0.99 mol) of ammoniumchloride at room temperature. The suspension was heated at 50° C. for0.5 hour, then cooled to room temperature and filtered. The residue waswashed with ethyl acetate, and the combined filtrate was evaporated todryness. The solid was basified with saturated sodium bicarbonatesolution, and extracted with ethyl acetate. The organic phase was driedover magnesium sulfate and evaporated to dryness to yield a brown solid(21 g, 83% yield), mp 83° C.;

¹H NMR (DMSO-d₆) δ 8.85 (broad s, 1H), 7.32 (d, J=2 Hz, 1H), 6.71 (d,J=8 Hz, 1H), 6.24 (dd, J=8 Hz, 2 Hz, 1H), 4.64 (s, 2H), 3.68 (s, 3H),2.05 (s, 3H); MS (ES) m/z 181.1 (M+1). Analysis for C₉H₁₂N₂O₂: Calcd: C,59.99; H, 6.71; N, 15.55. Found: C, 59.65; H, 6.63; N, 15.23.

REFERENCE EXAMPLE 52 Ethyl(E)-3-[3-(Acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate and Ethyl(Z)-3-[3-(Acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate

An amount of 4.95 g (0.0275 mol) of N-(5-amino-2-methoxyphenyl)acetamidewas heated with ethyl(ethoxymethylene)cyanoacetate (4.74 g, 0.028 mol),at 120° C. for 2 hours. The reaction mixture was evaporated to drynessto give a brown solid (7.9 g, 95% yield) with an Z/E isomer ratio of 2to 1, mp 155-160° C.;

¹H NMR (DMSO-d₆) (Z isomer) δ 10.7 (d, J=14 Hz, 1H), 9.27 (broad s, 1H),8.30 (d, J=14 Hz, 1H), 8.01 (broad s, 1H), 7.05 (m, 2H), 4.21 (m, 2H),3.83 (s, 3H), 2.10 (s, 3H), 1.25 (m, 3H); (E isomer) δ 10.9 (d, J=14 Hz,1H), 9.24 (broad s, 1H), 8.15 (d, J=14 Hz, 1H), 8.12 (broad s, 1H), 7.22(m, 2H), 4.21 (m, 2H), 3.83 (s, 3H), 2.10 (s, 3H), 1.25 (m, 3H); HRMS(EI) m/z 304.1290 (M+1). Analysis for C₁₅H₁₇N₃O₄: Calcd: C, 59.40; H,5.65; N, 13.85. Found: C, 59.03; H, 5.51; N, 13.55.

REFERENCE EXAMPLE 53N-(3-Cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide

An amount of 1 g (0.003 mol) of ethyl(E)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate and ethyl(Z)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate was addedto a stirring solution of biphenyl (16.3 mL, 0.10 mol) and diphenylether (48.8 mL, 0.30 mol) at 256° C. After stirring for 2 hours at 256°C., the reaction mixture was cooled to room temperature, diluted withdiethyl ether (130 mL), filtered, and evaporated to dryness to give agray solid (0.53 g, 62% yield), mp 305-310° C.;

¹H NMR (DMSO-d₆) δ 12.80 (s, 1H), 9.58 (s, 1H), 8.62 (s, 1H), 8.58 (m,1H), 7.52 (s, 1H), 3.97 (s, 3H), 2.20 (s, 3H); HRMS (EI) m/z 257.0793(M+1).

REFERENCE EXAMPLE 54N-(4-Chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide

An amount of 10 g (0.039 mol) ofN-(3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide wasstirred in 29 mL (0.31 mol) of phosphorus oxychloride, heated at 100° C.for 0.5 hour, and subsequently cooled to 0° C. To this was slowly addeda saturated solution of sodium bicarbonate and ethyl acetate to extractthe product. The organic phase was washed with saturated brine solution,dried over sodium sulfate, and evaporated to give a brown solid (9.8 g,73% yield), mp 230-235° C.;

¹H NMR (DMSO-d₆) δ 9.77 (s, 1H), 8.98 (s, 1H), 8.94 (s, 1H), 7.50 (s,1H), 4.11 (s, 3H), 2.25 (s, 3H); HRMS (EI) m/z 275.0466 (M+1).

REFERENCE EXAMPLE 55N-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl]acetamide

An amount of 9.7 g (0.035 mol) ofN-(4-chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide was stirred in 97ml of 2-ethoxyethanol. To this was added 2,4-dichloro-5-methoxyaniline(prepared by the procedure described in WO 8501939-A1) (7.4 g, 0.038mol), and 4.1 g (0.035 mol) pyridine hydrochloride, and the mixture washeated at 135° C. for 3 hours. The solvent was evaporated and the solidwas stirred in saturated sodium bicarbonate solution and extracted withethyl acetate. The organic phase was washed with saturated brinesolution, dried over sodium sulfate and evaporated to dryness to give abrown solid (10.7 g, 71% yield), mp 267-270° C.;

¹H NMR (DMSO-d₆) δ 9.28 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.83 (s,1H), 7.40 (s, 1H), 6.82 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 2.16 (s,3H); MS (ES) m/z 431.1 (M+1).

REFERENCE EXAMPLE 567-Amino-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile

An amount of 5.0 g (0.012 mol) ofN-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl]acetamidewas stirred in 37% hydrochloric acid (500 mL), and heated at 65° C. for1 hour. The mixture was evaporated to a slurry, stirred in saturatedsodium bicarbonate solution, and extracted with ethyl acetate. Theorganic phase was dried over sodium sulfate, filtered through a pad ofsilica gel, and evaporated to dryness to give a tan solid (1.9 g, 42%yield), mp 265° C. decomp.;

¹H NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.66 (s,1H), 7.23 (s, 1H), 6.98 (s, 1H), 5.93 (s, 2H), 3.96 (s, 3H), 3.84 (s,3H); MS (ES) m/z 389.2 (M+1). Analysis for C₁₈H₁₄Cl₂N₄O₂: Calcd: C,55.54; H, 3.63; N, 14.39. Found: C, 55.80; H, 3.78; N, 14.67.

REFERENCE EXAMPLE 57 4-Methoxy-3-nitroaniline

A solution of 4-amino-2-nitrophenol (10.0 g, 64.9 mmol), cesiumcarbonate (21 g, 64 mmol), and methyl iodide (9.22 g, 64.9 mmol) inacetonitrile (1500 mL) was heated at reflux for 5 hours. The mixture wascooled to room temperature and subsequently filtered, evaporated, andpurified by flash chromatography (chloroform) to give 5.03 g (46% yield)of a reddish oil.

¹H NMR (DMSO-d₆) δ 7.09-7.03 (m, 2H), 6.87 (d, J=3 Hz, 1H), 5.21 (bs,2H), 3.77 (s, 3H); HRMS (EI) m/z 168.0497 (M+1). Analysis for C₇H₈N₂O₃:Calcd: C, 50.00; H, 4.80; N, 16.66. Found: C, 50.20; H, 5.07; N, 16.60.

REFERENCE EXAMPLE 58 Ethyl(E)-2-Cyano-3-(4-methoxy-3-nitroanilino)-2-propenoate and Ethyl(Z)-2-Cyano-3-(4-methoxy-3-nitroanilino)-2-propenoate

A mixture of 200 mg (1.19 mmol) of 4-methoxy-3-nitroaniline and 203 mg(1.20 mmol) of ethyl(ethoxymethylene)cyanoacetate in toluene (20 mL) washeated at reflux for 18 hours. This mixture was cooled to roomtemperature and filtered. The solid was washed with diethyl ether, anddried to give 293 mg of a yellow solid (84% yield) with an Z/E isomerratio of 2 to 1, mp 186-190° C.;

¹H NMR (DMSO-d₆) (Z isomer) δ 10.86 (broad s, 1H), 8.32 (broad s, 1H),8.05 (d, J=3 Hz, 1H), 7.34 (dd, J=9 Hz, 3 Hz, 1H), 7.38 (d, J=9 Hz, 1H),4.17 (m, 2H), 3.92 (s, 3H); 1.24 (m, 3H); (E isomer) δ 10.75 (d, J=13Hz, 1H), 8.43 (d, J=13 Hz, 1H), 8.15 (d, J=3 Hz, 1H), 7.82 (dd, J=9 Hz,3 Hz, 1H), 7.38 (d, J=9 Hz, 1H), 4.17 (m, 2H), 3.92 (s, 3H); 1.24 (m,3H); HRMS (EI) m/z 291.0846 (M+1). Analysis for C₁₃H₁₃N₃O₅: Calcd: C,53.61; H, 4.50; N, 14.43. Found: C, 53.48; H, 4.52; N, 14.46.

REFERENCE EXAMPLE 596-Methoxy-7-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile

An amount of 3.0 g (10.31 mmol) of ethyl(E)-2-cyano-3-(4-methoxy-3-nitroanilino)-2-propenoate and(Z)-2-cyano-3-(4-methoxy-3-nitroanilino)-2-propenoate was added to astirring solution of biphenyl (50 mL, 0.32 mmol) and diphenyl ether (150mL, 0.95 mmol), and heated at reflux for 2.5 hours. The reaction mixturewas cooled to room temperature and subsequently filtered, washed withdiethyl ether, and evaporated to dryness. The crude solid was stirred inboiling ethyl acetate (2200 mL) for one hour, and subsequently filteredand evaporated to give a light brown solid (910 mg, 36% yield), mp305-309° C.;

¹H NMR (DMSO-d₆) δ 13.10 (broad s, 1H), 8.81 (s, 1H), 8.15 (s, 1H), 7.81(s, 1H), 4.02 (s, 3H); HRMS (EI) m/z 245.0440 (M+1).

REFERENCE EXAMPLE 60 N-(2-Ethoxy-5-mitrophenyl)acetamide

An amount of 100 g (0.649 mol) of 2-amino-4-nitrophenol was added to astirring solution of water (444 mL) and acetic anhydride (124 mL). Afterstirring for 5 hours at room temperature, the reaction mixture wasfiltered and the solid was subsequently washed with water, diethylether, and evaporated to dryness to give 125 g (0.637 mol) of crudeintermediate. This intermediate was stirred in N,N-dimethylformamide(822 mL), and to this was added 204 g (1.48 mol) of potassium carbonateand 726 g (4.66 mol) of ethyl iodide. The mixture was heated at refluxfor 18 hours, cooled to room temperature, and evaporated to dryness. Theobtained solid was mixed with water, filtered, and washed consecutivelywith water and diethyl ether, and evaporated to give a golden solid (117g, 82% yield), mp 195-198° C.;

¹H NMR (DMSO-d₆) δ 9.37 (bs, 1H), 8.98 (s, 1H), 7.98 (d, J=9 Hz, 1H),7.24 (d, J=9 Hz, 1H), 4.28 (q, J=7 Hz, 2H), 2.17 (s, 3H), 1.43 (t, J=7Hz, 3H).

REFERENCE EXAMPLE 61 N-(5-Amino-2-ethoxyphenyl)acetamide

An amount of 22.4 g (0.10 mole) of N-(2-ethoxy-5-nitrophenyl)acetamidewas treated, according to the procedure described for the preparation ofthe intermediate N-(5-amino-2-methoxyphenyl)acetamide (Reference Example51), to give 18.5 g (95% yield) of a reddish oil;

¹H NMR (DMSO-d₆) δ 8.69 (broad s, 1H), 7.30 (s, 1H), 6.72 (d, J=9 Hz,1H), 6.23 (d, J=9 Hz, 1H), 4.25 (broad s, 2H), 3.91 (q, J=6.9 Hz, 2H),2.06 (s, 3H), 1.29 (t, J=6.9 Hz, 3H); HRMS (EI) m/z 194.1075 (M+1).Analysis for C₁₀H₁₄N₂O₂0.43H₂O: Calcd: C, 59.44; H, 7.40; N, 13.77.Found: C, 59.83; H, 7.00; N, 13.40.

REFERENCE EXAMPLE 62 Ethyl(E)-3-[3-(Acetylamino)-4-ethoxyanilino]-2-cyano-9-propenoate and Ethyl(Z)-3-[3-(Acetylamino)-4-ethoxyanilino]-2-cyano-2-propenoate

An amount of 17.3 g (89.1 mmol) of N-(5-amino-2-ethoxyphenyl)acetamidewas treated, according to the procedure described for the preparation ofethyl (E)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate(Reference Example 62), to give 26.8 g (95% yield) of a beige solid withan Z/E isomer ratio of 3 to 1, mp 185-188° C.;

¹H NMR (DMSO-d₆) (Z isomer) δ 10.70 (d, J=14 Hz, 1H), 9.10 (broad s,1H), 8.29 (d, J=14 Hz, 1H), 7.99 (broad s, 1H), 7.03 (m, 2H), 4.23 (q,J=7 Hz, 2H), 3.34 (s, 3H), 2.11 (s, 3H), 1.26 (t, J=7 Hz, 6H); (Eisomer) δ 10.90 (d, J=14 Hz, 1H), 9.10 (broad s, 1H), 8.15 (d, J=14 Hz,1H), 8.10 (broad s, 1H), 7.19 (m, 2H), 4.12 (q, J=7 Hz, 2H), 3.34 (s,3H), 2.11 (s, 3H), 1.36 (t, J=7 Hz, 6H); HRMS (EI) m/z 317.1356 (M+1).Analysis for C₁₆H₁₉N₃O₄0.25H₂O: Calcd: C, 59.71; H, 6.11; N, 13.01.Found: C, 60.05; H, 6.03; N, 12.68.

REFERENCE EXAMPLE 63N-(3-Cyano-6-ethoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide

An amount of 2.0 g (6.31 mmol) of ethyl(E)-3-[3-(acetylamino)-4-ethoxyanilino]-2-cyano-2-propenoate and ethyl(Z)-3-[3-(acetylamino)-4-ethoxyanilino]-2-cyano-2-propenoate wastreated, according to the procedure described for the preparation ofN-(3-cyano-6-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide (ReferenceExample 53), to give 0.59 g (35% yield) of a brown solid, mp 240° C.(decomp);

¹H NMR (DMSO-d₆) δ 12.80 (broad s, 1H), 9.35 (s, 1H), 8.61 (s, 1H), 8.58(broad s, 1H), 7.50 (s, 1H), 4.20 (q, J=7 Hz, 2H), 2.22 (s, 3H), 1.44(t, J=7 Hz, 3H); HRMS (EI) m/z 271.0961 (M+1). Analysis forC₁₄H₁₃N₃O₃-0.25H₂O: Calcd: C, 60.97; H, 4.94; N, 15.23. Found: C, 60.73;H, 4.58; N, 15.21.

REFERENCE EXAMPLE 64N-(4-Chloro)-3-cyano-6-ethoxy-7-quinolinyl)acetamide

N-(3-Cyano-6-ethoxy-4-oxo-1,4-dihydro-7-quinolinyl)acetamide (406 mg,1.5 mmol) was treated with 5.0 mL of phosphorus oxychloride by themethod of Reference Example 54 to give 202 mg (46%) of a light yellowsolid, mp 202-204° C.;

¹H NMR(DMSO-d₆) δ 9.53 (broad s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 7.47(s, 1H), 4.40 (q, J=7 Hz, 2H), 2.27 (s, 1H), 1.49 (t, J=7 Hz, 3H); HRMS(EI) 289.0603 (M+1). Analysis for C₁₄H₁₂N₃O₂Cl: Calcd: C, 58.04; H,4.17; N, 14.50; Cl, 12.24. Found: C, 58.16; H, 4.18; N, 14.57; Cl,12.03.

REFERENCE EXAMPLE 65N-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-quinolinyl]acetamide

N-(4-Chloro-3-cyano-6-ethoxy-7-quinolinyl)acetamide (290 mg, 1 mmol) wasreacted with 191 mg (1 mmol) of 2,4-dichloro-5-methoxyaniline (preparedby the procedure described in WO 8501939-A1) by the procedure ofReference Example 55. The product was recrystallized from ethyl acetateto yield 146 mg (33%) of the title product as yellow crystals, mp245-248° C.;

¹H NMR(DMSO-d₆) δ 9.63 (s, 1H), 9.34 (s, 1H), 8.71 (s, 1H), 8.42 (s,1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 4.31 (q, J=7 Hz, 2H),3.86 (s, 3H), 2.23 (s, 3H), 1.48 (t, J=7 Hz, 3H); HRMS (ESI) 445.0823(M+1).

REFERENCE EXAMPLE 667-Amino-4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-3-quinolinecarbonitrile

N-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-6-ethoxy-7-quinolinyl]acetamide(100 mg, 0.225 mmol), was hydrolyzed by the method of Reference Example56, in a mixture of concentrated hydrochloric acid and water (2 1) togenerate 74 mg (81%) of the title compound as a yellow solid, mp230-233° C.;

¹H NMR(DMSO-d₆) δ 9.33 (broad s, 1H), 8.33 (s, 1H), 7.76 (s, 1H), 7.71(s, 1H), 7.28 (s, 1H), 7.04 (s, 1H), 5.96 (broad s, 2H), 2.60 (q, J=7Hz, 2H), 3.90 (s, 3H), 1.50 (t, J=7 Hz, 3H); HRMS (ESI) 403.0714 (M+1).Analysis for C₁₉H₁₆N₄O₂Cl₂: Calcd: C, 56.59; H, 4.00; N, 13.89; Cl,17.58. Found: C, 56.73; H, 4.11; N, 13.66; Cl, 17.23.

REFERENCE EXAMPLE 67 4-(2-Imidazol-1-ylethyl)morpholine

To a solution of imidazole (6.81 g, 0.1 mol) in 50 mL of acetonitrile atroom temperature was added sodium hydroxide (6.8 g, 0.17 mol). Themixture was stirred at room temperature for 30 minutes.Tetrabutylammonium hydrogen sulfate (1.35 g, 4 mmol) was added followedby 4-(2-chloroethyl)morpholine hydrochloride (20.5 g, 0.11 mol). Themixture was heated at reflux for 42 hours and then concentrated invacuo. The residue was purified by flash silica gel chromatographyeluting with a gradient of 5% methanol in diethyl ether to 20% methanolin diethyl ether to provide 4.20 g (23% yield) of4-(2-imidazol-1-ylethyl)morpholine as a yellow oil;

¹H NMR (DMSO-d₆) δ 2.39 (t, J=4 Hz, 4H), 2.59 (t, J=7 Hz, 2H), 3.55 (t,J=4 Hz, 4H), 4.06 (t, J=7 Hz, 2H), 6.85 (s, 1H), 7.17 (s, 1H), 7.62 (s,1H); MS (ES) m/z 182.0 (M+1). Analysis for C₉H₁₅N₃O-0.45H₂O: Calcd: C,57.09; H, 8.46; N, 22.19. Found: C, 57.20; H, 8.55; N, 22.11.

REFERENCE EXAMPLE 684-{2-[5-(Tributylstannyl)-1H-imidazol-1-yl]ethyl}morpholine

To 1 mL of N,N,N′,N′-tetramethylethylenediamine at −78° C. with stirringwas added 2.5M n-bultyl lithium in hexane (1.92 mL, 4.8 mmol). Themixture was warmed to −20° C. 4-(2-Imidazol-1-ylethyl)morpholine (362mg, 2.0 mmol) was added and the mixture was stirred at −20° C. for 30minutes and at room temperature for 30 minutes. The mixture was cooledto −20° C., and tributyltin chloride (1.63 g, 5.0 mmol) was added. Thereaction was warmed to room temperature, stirred for 20 hours, andpartitioned between ethyl acetate and water. The layers were separatedand the aqueous layer was extracted with ethyl acetate. The combinedextracts were washed with brine, dried over magnesium sulfate andfiltered. Removal of the solvent in vacuo gave a residue which aspurified by flash silica gel chromatography eluting with 10% methanol inethyl acetate to provide 124 mg (13% yield) of4-{2-[5-(tributylstannyl)-1H-imidazol-1-yl]ethyl}morpholine as a yellowoil;

¹H NMR (DMSO-d₆) δ 0.86 (t, J=7 Hz, 9H), 1.07 (m, 6H), 1.29 (m, 6H),1.48 (m, 6H), 2.38 (t, J=4 Hz, 4H), 2.57 (t, J=7 Hz, 2H), 3.56 (t, J=4Hz, 4H), 4.00 (t, J=7 Hz, 2H), 6.83 (s, 1H), 7.84 (s, 1H); MS (ES) m/z472.2 (M+1). Analysis for C₂₁H₄₁N₃OSn: Calcd: C, 53.63; H, 8.79; N,8.94. Found: C, 53.26; H, 8.82; N, 8.99.

REFERENCE EXAMPLE 69 4-[(4-Bromo-3-thienyl)methyl]morpholine

Using an analogous procedure to that described for Reference Example 23,4-[(4-bromo-3-thienyl)methyl]morpholine was prepared from4-bromo-3-thiophenecarbaldehyde (prepared according to the procedure ofU.S. Pat. No. 4,332,952) and morpholine in 55% yield as a colorless oil;

¹H NMR (DMSO-d₆) δ 2.41 (t, J=5 Hz, 4H), 3.42 (s, 2H), 3.56 (t, J=5 Hz,4H), 7.48 (d, J=3 Hz, 1H), 7.67 (d, J=3 Hz, 1H); MS (ES) m/z 262.1(M+1).

REFERENCE EXAMPLE 70 4-[(3-Bromo-2-thienyl)carbonyl]morpholine

Using an analogous procedure to that described for Reference Example 27,(4-[(3-bromo-2-thienyl)carbonyl]morpholine was prepared from3-bromo-2-thiophenecarboxylic acid and morpholine in 83% yield as acolorless oil;

¹H NMR (DMSO-d₆) δ 3.34 (t, J=5 Hz, 4H), 3.63 (t, J=5 Hz, 4H), 7.15 (d,J=5 Hz, 1H), 7.79 (d, J=5 Hz, 1H); MS (ES) m/z 276.1 (M+1). Analysis forC₉H₁₀BrNO₂S: Calcd: C, 39.14; H, 3.65; N, 5.07. Found: C, 39.08; H,3.55; N, 5.07.

REFERENCE EXAMPLE 71 4-[(3-Bromo-2-thienyl)methyl]morpholine

4-[(3-Bromo-2-thienyl)carbonyl]morpholine (927 mg, 3.36 mmol) wasdissolved in 17 mL of tetrahydrofuran and borane-dimethyl sulfidecomplex (0.67 mL, 6.71 mmol) was added dropwise via (syringe. Themixture was heated at reflux for 30 minutes. Methanol (10 mL) was addedand the solution was evaporated to dryness. Another 10 mL of methanolwas added and the solution was evaporated again and sodium hydroxide(2.5M, 5.0 mL) and ethanol (10 mL) were added to the residue. Themixture was stirred at room temperature overnight, diluted with brineand extracted with ethyl acetate (50 mL×3). The combined extracts weredried over sodium sulfate, filtered and concentrated in vacuo to give879 mg (100%) of 4-[(3-bromo-2-thienyl)methyl]morpholine as a colorlessoil;

¹H NMR (DMSO-d₆) δ 2.43 (t, J=5 Hz, 4H), 3.57 (t, J=5 Hz, 4H), 3.65 (s,2H), 7.04 (d, J=5 Hz, 1H), 7.60 (d, J=5 Hz, 1H); MS (ES) m/z 262.1(M+1). Analysis for C₉H₁₂BrNOS: Calcd: C, 41.23; H, 4.61; N, 5.34.Found: C, 41.06; H, 4.53; N, 5.40.

REFERENCE EXAMPLE 72 2-(Methylsulfonyl)ethylamine Hydrochloride Salt

Using an analogous procedure to that described for Reference Example 49,2-(methylsulfonyl)ethylamine hydrochloride salt was prepared frommethanesulphonylacetonitrile in 87% yield as a white solid, mp 131-133°C.;

¹H NMR (DMSO-d₆) δ 63.12 (s, 3H), 3.22 (t, J=7 Hz, 2H), 3.51 (t, J=7 Hz,2H), 8.30 (s, 3H); MS (ES) m/z 124.0 (M+1).

REFERENCE EXAMPLE 73 4-[(5-Bromo-3-thienyl)methyl]morpholine

Using in analogous procedure to that described for Reference Example 23,4[(5-bromo-3-thienyl)methyl]morpholine was prepared from5-bromo-3-thiophenecarbaldehyde (prepared according to the procedure ofU.S. Pat. No. 5,597,832) and morpholine in 69% yield as a colorless oil;

¹H NMR (DMSO-d₆) δ 2.33 (t, J=5 Hz, 4H), 3.40 (s, 2H), 3.56 (t, J=5 Hz,4H), 7.11 (d, J=2 Hz, 1H), 7.34 (d, J=2 Hz, 1H); MS (ES) m/z 262.0(M+1).

REFERENCE EXAMPLE 747-Bromo-4-(2-chloro-4-fluoro-5-methoxyanilino)-3-quinolinecarbonitrile

A mixture of 2-chloro-4-fluoro-5-methoxy aniline (prepared by theprocedure described in WO 8501939 A1) (300 mg, 1.71 mmol),7-bromo-4-chloro-3-quinolinecarbonitrile (400 mg, 1.5 mmol) and pyridinehydrochloride (170 mg, 1.47 mmol) in 4 mL of ethoxyethanol was heated atreflux for 1.5 hours and concentrated. The residue was treated withsaturated sodium bicarbonate and the resulting precipitate was collectedby filtration and dried. The product was dissolved in ethyl acetate andfiltered through hydrous magnesium silicate. The filtrate wasconcentrated, and the resulting solid was purified by flash silica gelchromatography, eluting with 1:1 hexane:ethyl acetate to give 400 mg(66% yield) of7-bromo-4-(2-chloro-4-fluoro-5-methoxyanilino)-3-quinolinecarbonitrileas a white solid, mp 200-202° C.; MS (ES) m/z 405.9 (M+1). Analysis forC₁₇H₁₀BrClFN₃O-0.2H₂O: Calcd: C, 49.78; H, 2.56; N, 10.24. Found: C,49.64; H, 2.46; N, 10.01.

REFERENCE EXAMPLE 757-Bromo-4-(2-chloro-5-methoxy-4-methylanilino)-3-quinolinecarbonitrile

A mixture of 2-chloro-4-methyl-5-methoxy aniline (prepared by theprocedure described in Theodoridis, G., Pesticide Science, 30(3), 259(1990) (265 mg, 1.71 mmol), 7-bromo-4-chloro-3-quinolinecarbonitrile(400 mg, 1.5 mmol) and pyridine hydrochloride (170 mg) in 4 mL ofethoxyethanol was heated at reflux for 1.5 hours and concentrated. Theresidue was treated with saturated sodium bicarbonate and the resultingprecipitate was collected by filtration and dried. The product wasdissolved in ethyl acetate and filtered through hydrous magnesiumsilicate. The filtrate was concentrated, and the resulting solid waspurified by flash silica gel chromatography, eluting with 3:1hexane:ethyl acetate to give 210 mg (35% yield) of7-bromo-4-(2-chloro-5-methoxy-4-methylanilino)-3-quinolinecarbonitrileas a white solid, mp 215-2170° C.;

¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 8.55 (s, 1H), 8.50 (d, J=9 Hz, 1H),8.13 (s, 1H), 7.84 (d, J=9 Hz, 1H), 7.37 (s, 1H), 7.14 (s, 1H), 3.79 (s,3H), 2.20 (s, 3H), MS (ES) m/z 402.0 (M+1). Analysis for C₁₈H₁₃BrClN₃O:Calcd: C, 53.69; H, 3.25; N, 10.44. Found: C, 53.60; H, 3.43; N, 10.28.

REFERENCE EXAMPLE 76 6-(4-Morpholinylmethyl)-3-pyridinyl4-Methylbenzenesulfonate

To a solution of 6-formyl-3-pyridinyl 4-methylbenzenesulfonate (2.77 g,10 mmol, prepared according to the procedure of Ross, S. T., J. Med.Chem., 30, 1309 (1987) in 50 mL of methyl alcohol at room temperaturewas added morpholine (1.74 g, 20 mmol). The mixture was stirred at roomtemperature for one hour. Sodium cyanoborohydride (2.51 g, 40 mmol) wasadded in portions. The mixture was stirred at room temperature for onehour, and concentrated. The residue was partitioned between ethylacetate and brine. The layers were separated and the organic layer wasdried over magnesium sulfate. Removal of the solvent in vacuo gave aresidue which was purified by silica gel chromatography eluting withethyl acetate to provide 1.12 g (32% yield) of6-(4-morpholinylmethyl)-3-pyridinyl 4-methylbenzenesulfonate as a whitesolid, mp) 68-69° C.;

¹H NMR (DMSO-d₆) δ 2.36 (t, J=5 Hz, 4H), 2.43 (s, 3H), 3.56 (s, 2H),3.57 (t, J=5 Hz, 4H), 7.51 (m, 4H), 7.75 (d, J=9 Hz, 2H), 8.13 (dd, J=2,1 Hz, 1H); MS (ES) m/z 349.1 (M+1). Analysis for C₁₇H₂₀N₂O₄S-0.45H₂O:Calcd: C, 57.27; H, 5.91; N, 7.86. Found: C, 57.17; H, 5.64; N, 8.07.

REFERENCE EXAMPLE 77 6-(4-Morpholinylmethyl)-3-pyridinylTrifluoromethanesulfonate

A suspension of 6-(4-morpholinylmethyl)-3-pyridinyl4-methylbenzenesulfonate (800 mg, 2.30 mmol) in 50 mL of 2.5M sodiumhydroxide in water was heated at reflux for one hour, until homogeneous.The mixture was cooled to room temperature, and neutralized withconcentrated hydrochloric acid to pH 7. The solvent was removed in vacuoto give a white powder. To a suspension of this residue in 25 mL ofdichloromethane at room temperature was added 2,6-lutidine (1.07 g, 10mmol) followed by trifluoromethanesulfonic anhydride (2.82 g, 10 mmol).The mixture was stirred at room temperature for 30 minutes, and quenchedwith saturated sodium carbonate solution. The layers were separated andthe aqueous layer was extracted with dichloromethane. The combinedextracts were dried over magnesium sulfate, and filtered through hydrousmagnesium silicate. Removal of the solvent in vacuo gave a residue whichwas purified by silica gel chromatography eluting with ethyl acetate toprovide 112 mg (15% yield) of 6-(4-morpholinylmethyl)-3-pyridinyltrifluoromethanesulfonate as a brown oil;

¹H NMR (DMSO-d₆) δ 3.40 (s, 4H), 3.74 (s, 2H), 3.92 (s, 2H), 4.58 (s,2H), 7.77 (d, J=9 Hz, 1H), 8.23 (dd, J=9, 3 Hz, 1H), 8.93 (d, J=3 Hz,1H); MS (ES) m/z 327.0 (M+1).

REFERENCE EXAMPLE 78 7-Nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile

A mixture of 50 g (0.361 mol) of 3-nitroaniline and 61.85 g (0.366 mol)of ethyl(ethoxymethylene)cyanoacetate was heated at 120° C. for 3 hours.This mixture was cooled to room temperature and filtered. The solid waswashed with diethyl ether, and dried to give 95 g of ethyl2-cyano-3-(3-nitroanilino)-2-propenoate as a yellow solid (quantitativeyield).

An amount of 12 g (45.98 mmol) of ethyl2-cyano-3-(3-nitroanilino)-2-propenoate was added to a refluxingsolution (750 mL) of biphenyl and diphenyl ether (1:3 ratio) andrefluxed for 8 hours. The reaction mixture was cooled to roomtemperature and subsequently filtered, washed with diethyl ether, andevaporated to dryness to give a brown solid (6.5 g, 66% yield,containing 20% of the 5-nitro-isomer);

HRMS (EI) 214.02618 (M−1). Analysis for C₁₀H₅N₃O₃-0.17H₂O: Calcd: C,55.05; H, 2.46; N, 19.26. Found: C, 55.19; H, 2.22; N, 19.35.

REFERENCE EXAMPLE 79 4-Chloro-7-nitro-quinoline-3-carbonitrile

An amount of 5.5 g (0.026 mol) of7-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (Reference Example78) was stirred in 38 mL (0.41 mol) of phosphorus oxychloride, heated toreflux for 3 hours, and subsequently cooled to 0° C. To this was slowlyadded ice water and a saturated solution of sodium bicarbonate. Afterstirring for 0.5 hour, the mixture was filtered, and the solids weresubsequently washed with water and dried to give a brown solid (5.5 g,91% yield; contains 20% 5-nitro-isomer), mp 275° C. decomp;

MS (ES) m/z 233.1 (M−1).

REFERENCE EXAMPLE 804-(2,4-Dichloro-5-methoxyanilino)-7-nitro-quinoline-3-carbonitrile

An amount of 3.0 g (0.013 mol) of4-chloro-7-nitro-quinoline-3-carbonitrile was stirred in 30 mL of2-ethoxyethanol. To this were added 2,4-dichloro-5-methoxyaniline(prepared by the procedure of WO 8501939-A1) (2.7 g, 0.014 mol), and 1.6g (0.005 mol) pyridine hydrochloride and the mixture was heated at 80°C. for 2 hours. The solvent was evaporated, washed with ethyl acetateand dried to give a brown solid (5.3 g, 105%). The ethyl acetate washwas subsequently stirred with saturated bicarbonate solution, saturatedbrine solution, dried over sodium sulfate, and evaporated. The orangeoily residue was purified by preparative thin layer chromatography (10%hexane in ethyl acetate), to give an orange solid (86 mg; contains 17%5-nitro-isomer), mp 112-115° C.;

MS (ES) m/z 389.0 (M+1); HRMS (EI) m/z 389.01895 (M+1). Analysis forC₁₇H₁₀Cl₂N₄O₃: Calcd: C, 52.46; H, 2.59; N, 14.40. Found: C, 52.53; H,2.67; N, 14.11.

REFERENCE EXAMPLE 817-Amino-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

An amount of 4 g of4-(2,4-dichloro-5-methoxyanilino)-7-nitro-3-quinolinecarbonitrileHCl-salt (Reference Example 80) was stirred in 100 mL of methanol and 25mL of water, and to this was added at room temperature 2.9 g (0.052 mol)of iron powder. The suspension was heated to reflux for 3 hours, thencooled to room temperature and filtered. The residue was stirred withsaturated bicarbonate solution and ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate, and evaporated to give atan solid (1.7 g, 46% yield; contains 17% 5-amino-isomer), mp 230-232°C.;

MS (ES) m/z 359.0 (M+1); HRMS (EI) m/z 359.04457 (M+1). Analysis forC₁₇H₁₂Cl₂N₄O: Calcd: C, 55.40; H, 3.53; N, 15.21. Found: C, 55.42; H,3.75; N, 15.03.

REFERENCE EXAMPLE 827-Bromo-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile

A mixture of 3-methyl-4-(2-pyridinylmethoxy)aniline (prepared by theprocedure described in U.S. Pat. No. 5,955,464) (822 mg, 3.84 mmol),7-bromo-4-chloro-3-quinolinecarbonitrile (935 mg, 3.5 mmol) and pyridinehydrochloride (406 mg) in 20 mL of ethoxyethanol was heated at refluxfor 20 minutes. The reaction mixture was filtered while warm and thesolids were washed with ethoxyethanol and diethyl ether. The solids werethen suspended in 20 mL of water and 6 mL of concentrated aqueousammonium hydroxide was added and the mixture was stirred for 30 min. Thesolids were collected washing with water to provide 1.335 g (86% yield)of7-bromo-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrileas a tan solid, mp 238-241° C.;

MS (ES) m/z 445.1, 447.0 (M+1). Analysis for C₂₃H₁₇BrN₄O-2.0H₂O: Calcd:C, 57.39; H, 4.40; N, 11.64. Found: C, 57.54; H, 4.33; N, 11.69.

REFERENCE EXAMPLE 834-(2,4-Dichloro-5-methoxyanilino)-7-tributylstannanyl-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile (790mg, 1.67 mmol) (Reference Example 13), bis(tributyltin) (0.97 mL, 1.91mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg) intriethylamine (5.71 mL) and N,N-dimethylformamide (1.71 mL) was heatedat 100-105° C. for 16 hours. The reaction mixture was evaporated and theresidue was purified by flash column chromatography to give 645 mg (61%)of4-(2,4-dichloro-5-methoxyphenylamino)-7-tributylstannanyl-3-quinolinecarbonitrileas a light yellow solid: mp 108-110° C.; MS (M+H)+.

REFERENCE EXAMPLE 842-[[(6-Bromo-3-pyridinyl)methyl](methyl)amino]ethanol

A mixture of 2-bromo-5-(bromomethyl)pyridine (470 mg, 1.87 mmol)(prepared by the procedure described in Windscheif, P. M., Synthesis,87(1994) and 2-(methylamino)ethanol (935 mg, 12.4 mmol) in 10 mL ofacetonitrile was stirred at room temperature for 16 hours thenconcentrated. The residue was partitioned between 5% aqueous sodiumcarbonate solution and ethyl acetate. The organic layer was separated,dried, and concentrated. The residue was purified by flash columnchromatography, eluting with a gradient of ethyl acetate to 10% methanolin ethyl acetate to provide 362 mg (79%) of2-[[(6-bromo-3-pyridinyl)methyl](methyl)amino]ethanol as a yellow oil,:MS 245.2 (M+H)+.

REFERENCE EXAMPLE 85 1-(6-Chloro-3-pyridinyl)-4-ethylpiperazine

A mixture of 5-bromo-2-chloropyridine (384 mg, 2.0 mmol),1-ethylpiperazine (228 mg, 2.0 mmol), sodium tert-butoxide (576 mg, 6mmol), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg, 0.02 mmol),and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (23.6 mg,0.06 mmol) in 10 mL of toluene was heated at reflux for 1 hour andconcentrated. The residue was purified by flash column chromatography,eluting with 5% methanol in ethyl acetate to provide 269 mg (60%) of1-(6-chloro-3-pyridinyl)-4-ethylpiperazine as a brown semi-solid: MS225.9 (M+H)+.

REFERENCE EXAMPLE 86 1-(6-Bromo-3-pyridinyl)-4-ethylpiperazine

1-(6-Chloro-3-pyridinyl)-4-ethylpiperazine (903 mg, 4.0 mmol) in 30 mLof phosphorus tribromide was heated at 150° C. for four days and cooledto room temperature. The mixture was then poured onto an ice-watermixture, and the solution was neutralized with sodium carbonate. Theproduct was extracted with ethyl acetate. The organic layer wasseparated, dried, and concentrated. The residue was purified by flashcolumn chromatography, eluting with 5% methanol in ethyl acetate toprovide 940 mg (87%) of 1-(6-bromo-3-pyridinyl)-4-ethylpiperazine as abrown solid: mp 30-31° C.; MS 269.8 (M+H)+.

REFERENCE EXAMPLE 87 3-Furyl(4-nitrophenyl)methanol

To a solution of 3-bromofuran (10.28 g, 70 mmol) in 200 mL oftetrahydrofuran at −78° C. was added n-butyllithium (2.5M in hexanes,26.4 mL, 66 mmol). The solution was stirred at −78° C. for 10 minutes. Asolution of 4-nitrobenzaldehyde (9.06 g, 60 mmol) in 80 mL oftetrahydrofuran was added, and the mixture was stirred at −78° C. for 10min then warmed to room temperature. The reaction was quenched with anaqueous ammonium chloride solution, and the product was extracted withethyl acetate. The organic layer was washed with saturated sodiumchloride solution, dried over magnesium sulfate, and concentrated. Theresidue was purified by flash column chromatography, eluting with agradient of 10% ethyl acetate in hexanes to ethyl acetate/hexanes (1:1)to provide 7.83 g (60%) of 3-furyl(4-nitrophenyl)methanol as a yellowsolid: mp 50-52° C.; MS 219.0 (M+H)+.

REFERENCE EXAMPLE 88 4-(3-Furylmethyl)aniline

A mixture of 3-furyl(4-nitrophenyl)methanol (658 mg, 3.0 mmol) andpalladium hydroxide (20 wt. % on carbon, 100 mg) in 20 mL of methanolwas hydrogenated at 50 psi for 8 minutes, and filtered. The filtrate wasconcentrated, and the residue was purified by flash columnchromatography, eluting with ethyl acetate/hexanes (1:2) to provide 253mg (49%) of 4-(3-furylmethyl)aniline as a tan oil: MS: 174.2 (M+H)+.

REFERENCE EXAMPLE 89 3-Chloro-4-phenoxyaniline

A mixture of 3-chloro-4-fluoronitrobenzene (17.6 g, 0.1 mol), phenol(18.8 g, 0.2 mol), and sodium bicarbonate (25.2 g, 0.3 mol) in 200 mL ofdimethylsulfoxide was heated at 80° C. for 30 minutes and then cooled toroom temperature. The mixture was treated with saturated sodium chloridesolution, and the product was extracted with ethyl acetate. The organiclayer was washed with 0.1 N sodium hydroxide solution, water (×4) andsaturated sodium chloride, dried over magnesium sulfate andconcentrated. The residue was dissolved in a mixture of 100 mL ofmethanol and 100 mL of glacial acetic acid. Iron powder (22,4 g, 0.4mol) was added, and the mixture was heated at reflux for 1 hour, cooledto room temperature, and filtered through Celite. The filtrate wasconcentrated, and the residue was treated with saturated sodiumbicarbonate solution. The product was extracted with ethyl acetate. Theorganic layer was washed with saturated sodium chloride, dried overmagnesium sulfate and filtered through Magnesol. Removal of the solventprovided 19.6 g, (89%) of 3-chloro-4-phenoxyaniline as a brown solid:

mp 31-33° C.; MS: 220.0 (M+H)+.

REFERENCE EXAMPLE 90 3-Chloro-4-(phenylthio)aniline

Using an analogous procedure to that described for Reference Example 89,replacement of phenol with thiophenol provided3-chloro-4-(phenylthio)aniline as a brown solid in 58% yield: mp 48-50°C.; MS 236.0 (M+H)+.

REFERENCE EXAMPLE 91 1-(5-Bromo-2-pyridinyl)-4-piperidinol

A mixture of 2,5-dibromopyridine (1.00 g, 4.20 mmol),4-hydroxypiperidine (4.25 g, 42 mmol) in 10 mL of acetonitrile washeated at reflux for 20 hours. After cooling, the mixture wasconcentrated and the residue was treated with water. The aqueoussuspension was extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate and filtered. Removal ofthe solvent gave a solid residue that was purified by flash columnchromatography eluting with a gradient of 20% ethyl acetate in hexanesto 50% ethyl acetate in hexanes to provide 1.02 g (94.0%) of1-(5-bromo-2-pyridinyl)-4-piperidinol as white rosette crystals: mp91-93° C.; MS 257.2 (M+H)+.

REFERENCE EXAMPLES 92 AND 93 5-Bromo-2-(dibromomethyl)pyrdine and5-Bromo-2-(bromomethyl)pyridine

A mixture of 5-bromo-2-methylpyridine (2.00 g, 11.6 mmol),N-bromosuccinimide (2.17 g, 12.2 mmol) and 2,2′-azabisisobutyronitrile(19.1 mg, 0.12 mmol) was heated at reflux in 30 mL of carbontetrachloride under irradiation with a 300 Watt lamp. After 6 hours, themixture was allowed to cool, the succinimide was filtered off, and thefiltrate was concentrated in vacuo. Chloroform as added and the organiclayer washed with saturated aqueous sodium bicarbonate, dried oversodium sulfate and concentrated to a solid residue that was purified byflash chromatography eluting with a gradient of 2% ethyl acetate inhexanes to 8% ethyl acetate in hexanes to provide 2.4 g (25%) of5-bromo-2-(dibromomethyl)pyridine as a yellow solid: mp 59-61° C.; alongwith 5-bromo-2-(bromomethyl)pyridine (47%). (The preparation of5-bromo-2-(bromomethyl)pyridine is reported in Bioorg. Med. Chem. Lett,4, 99-104, 1994).

REFERENCE EXAMPLE 94 5-Bromo-2-pyridinecarbaldehyde

A mixture of 5-bromo-2-(dibromomethyl)pyridine (2.28 g, 9.51 mmol)(Reference Example 92) in 7 mL of morpholine was stirred at roomtemperature overnight. The mixture was partitioned between ethyl acetateand water. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash column chromatography eluting with a gradient of 3% methanol indichloromethane to 10% methanol in dichloromethane to provide 0.79 g(44%) of 5-bromo-2-pyridinecarbaldehyde as an off-white solid: mp 90-92°C.; MS 186.0 (M+H)+.

REFERENCE EXAMPLE 95 1-[(5-Bromo-2-pyridinyl)methyl]-4-piperidinol

A mixture of 5-bromo-2-(bromomethyl)pyridine (600 mg, 2.4 mmol)(Reference Example 93), 4-hydroxypiperidine (293 mg, 2.9 mmol) and1,1-diisopropylethylamine (308 mg, 2.4 mmol) in 5 mL of acetonitrile wasstirred at room temperature for 1 hour. The reaction mixture was treatedwith brine and the product was extracted with ethyl acetate. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography eluting with a gradient of 3% methanol in dichloromethaneto 10% % methanol in dichloromethane to provide 496 mg (76%) of1-[(5-bromo-2-pyridinyl)methyl]-4-piperidinol as an off-white solid: mp52-54° C.; MS 217.18 (M+H)+.

REFERENCE EXAMPLE 96 4-{4-[(5-Bromo-2-pyridinyl)oxy]benzyl}morpholine

To a solution of 4-hydroxybenzaldehyde (2.0 g, 16.4 mmol), morpholine(1.4 g, 16.4 mmol) and acetic acid (1.2 g, 20.6 mmol) in 60 mL ofanhydrous ethanol was added sodium cyanoborohydride (1.3 g, 21.3 mmol)in portions. The resulting mixture was stirred at room temperatureovernight and then concentrated in vacuo. The residue was treated withwater and neutralized with 6 N HCl. The aqueous solution was extractwith ether and then treated with 28% aqueous ammonium hydroxide. Thebasified aqueous solution was extracted with ethyl acetate. The ethylacetate phase was washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo. The residue was purified by flash columnchromatography eluting with 80% ethyl acetate in hexanes to all ethylacetate to 2% methanol in ethyl acetate to 5% methanol in ethyl acetateto provide 2.09 g (66%) of the intermediate phenol as a white solid.

The intermediate phenol was added in portions to a suspension of sodiumhydride (304 mg, 7.60 mmol) in 6 mL of dimethylformamide. The reactionmixture was stirred at room temperature for 10 minutes. A solution of2,5-dibromopyridine (1.5 g, 6.33 mmol) in 4 mL of dimethylformamide wasadded. The resulting dark solution was heated at 80° C. for 17 hours andthen at 150° C. for 7 hours. After cooling to room temperature, themixture was concentrated in vacuo. The residue was treated with waterand extracted with dichloromethane. The organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography eluting with 50%ethyl acetate in hexanes to provide 1.70 g (77%) of4-{4-[(5-bromo-2-pyridinyl)oxy]benzyl)morpholine as yellow oil: MS 349.0(M+H)+.

REFERENCE EXAMPLE 97 1-[(4-Bromo-2-thienyl)methyl]-4-methylpiperazine

N-Methylpiperazine (0.65 g, 6.5 mmol) was added to a solution of4-bromo-2-thiophenecarboxaldehyde (0.975 g, 5.0 mmol) in 30 mL ofmethylene chloride and 4 mL of dimethylformamide. The mixture was cooledto 0° C. and sodium triacetoxyborohydride (2.75 g, 13.0 mmol) was added.After stirring at 0° C. for 1.5 hours, a catalytic amount of acetic acidwas added and the reaction mixture was allowed to warm to roomtemperature and stirred for 2 hours. The reaction was quenched by theaddition of water and then partitioned between saturated sodiumbicarbonate and methylene chloride. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuum. The residue waspurified by column chromatography, eluting with chloroform to provide0.7 g (48%) of 1-[(4-bromo-2-thienyl)methyl]-4-methylpiperazine as aviscous liquid: MS 276.8 (M+H)+.

REFERENCE EXAMPLE 98 3-(2-Chloro-4-nitrobenzyl)furan

To a −78° C. solution of 3-bromofuran (3.2 mL, 35.60 mmol) in 40 mL oftetrahydrofuran was added tert-butyl lithium (42 mL of a 1.7 M solutionin hexanes, 71.4 mmol) over 7 minutes. The reaction mixture was allowedto warm to −45° C. and then cooled again to −78° C. After stirring for50 minutes, a solution of 2-chloro-4-nitrobenzaldehyde (5.32 g, 28.68mmol) (prepared by the procedure described in U.S. Pat. No. 5,807,876)in 15 mL of tetrahydrofuran was added over 5 minutes. The reactionmixture was allowed to warm to room temperature and quenched with anaqueous solution of saturated ammonium chloride. The aqueous layer wasextracted with diethyl ether. The organic layers were combined, washedwith brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by flash column chromatography elutingwith 10% ethyl acetate in hexanes to provide 2.60 g (36%) of theintermediate carbinol as an oil. The above procedure was repeated toprovide additional amounts of the carbinol.

To a suspension of the intermediate carbinol (3.70 g 14.59 mmol) andsodium iodide (8.74 g, 58.35 mmol) in 15 mL of acetonitrile on a waterbath was added dimethyl dichlorosilane (3.45 mL, 29.17 mmol). Theresulting mixture was stirred for 20 min then poured into ethyl acetate.The organic layer was washed with water, saturated sodium bicarbonate,saturated sodium thiosulfate and brine, then dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash column chromatography eluting with 1% ethyl acetate in hexanes toprovide 2.50 g (72%) of 3-(2-chloro-4-nitrobenzyl)furan as an oil: MS(CI) 237.98 (M+H)+.

REFERENCE EXAMPLE 99 3-Chloro-4-(2-furylmethyl)aniline

A mixture of 3-(2-chloro-4-nitrobenzyl)furan (2.50 g, 10.52 mmol), ironpowder (3.70 g, 66.25 mmol), ammonium chloride (5.60 g, 106 mmol) in 40mL of water and 80 mL of methanol was heated at reflux for 6 hours. Themixture was cooled and filtered through a pad of Celite washing withethyl acetate. The filtrate was concentrated to remove the ethyl acetateand methanol. The aqueous residue was partitioned between water andethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography eluting with 10% ethyl acetatein hexanes to provide 2.27 g (97%) of 3-chloro-4-(2-furylmethyl)anilineas a light yellow oil:

MS (ES) 207.9 (M+H)+.

The Reference Examples in Table 3 are listed with the chemical name,melting point and/or mass spectral data and the Reference Exampleprocedure used in the preparation of the compound.

TABLE 3 Ref. Ref. Chemical MP mass Ex. Ex. Name ° C. spec. pro. 1006-bromo-4-({3-chloro-4- 275-277 470.0 13 [(1-methyl-1H-imidazol-2-yl)-(M + H) + sulfanyl)phenyl}-amino)-3- quinolinecarbonitrile 1017-bromo-4-(4-chloro-5-  97-100 402.0, 404.0  8methoxy-2-methylanilino)-3- (M + H) + quinolinecarbonitrile 1027-bromo-4-(2-chloro-5- 185-187 390.0 13 methoxy-anilino)-3-quinoline-(M + H) + carbonitrile 103 7-bromo-4-(5-methoxy-2- 208-210 368.1 13methylanilino)-3-quinoline- (M + H) + carbonitrile 1044-[4-(benzyloxy)-3-chloro- 223-225 466.0 13anilino]-7-bromo-3-quinoline- (M + H) + carbonitrile 1057-bromo-4-(3,4,5-trimethoxy- 224-226 414.0, 13anilino)-3-quinolinecarboni- 416.0 trile (M + H) + 1067-bromo-4-[3-chloro-4-  237 465.9 13 (phenylsulfanyl)anilino)-3- (dec)(M + H) + quinolinecarbonitrile 107 7-bromo-4-(3-chloro-4-phe-  210450.0 13 noxyanilino)-3-quinoline- (dec) (M + H) + carbonitrile 1087-bromo-4-(2,4-dimethyl- 170-172 352.0 13 anilino)-3-quinoline- (M +H) + carbonitrile 109 7-bromo-4-(4-bromo-2- 188-190 449.9  6chloro-6-methylanilino)-3- (M + H) + quinolinecarbonitrile 1107-bromo-4-(3-chloro-4-(3- 208-210 439.7 13 furylmethyl)anilino]-3- (M +H) + quinolinecarbonitrile 111 7-bromo-4-[4-(3-furylmethyl)- 180-182405.7 13 anilino]-3-quinoline- (M + H) + carbonitrile 1124-{3-chloro-4-[(1-methyl-1H- dec 517.5, 14 imidazol-2-yl)sulfanyl] >240519.7 anilino}-7-iodo-3-quinoline- (M + H) + carbonitrile 1134-[3-chloro-4-(phenyl- 240-245 514 13 fanyl)-anilino-7-iodo-3- (M + H) +quinolinecarbonitrile 114 4-(3-chloro-4-phenoxy- 182-184 497.9 13anilino)-7-iodo-3-quino- (M + H) + linecarbonitrile 1157-iodo-4-(3,4,5-trimethoxy- 220-222 461.7, 13 anilino)-3-quinoline-462.7 carbonitrile (M + H) + 116 4-(2,4-dimethylanilino)- >250 400.7 137-iodo-3-quinoline- (M + H) + carbonitrile 117 4-(4-bromo-2-chloro-6-140-142 497.4 13 methylanilino)-7-iodo- (M + H) +3-quinolinecarbonitrile 118 4-[4-(3-furylmethyl)- 193-195 451.70 13anilino]-7-iodo-3- (M + H) + quinolinecarbonitrile 1194-[3-chloro-4-(3-furylmethyl)- 163-165 485.7 13anilino]-7-iodo-3-quinoline- (M + H) + carbonitrile 1204-{3-chloro-4-[(1-methyl- 570.3 22 1H-imidazol-2-yl)sulfanyl] (M + H) +anilino}-3-cyano-6-methoxy- 7-quinolinyl trifluoromethane- sulfonate 1214-(5-bromo-2-pyridinyl)- 73-74 243 91 morpholine (M + H) + 1221-[(6-bromo-3-pyridinyl)- oil 270 84 methyl]-4-methylpiperazine (M +H) + 123 5-bromo-N-[2-(4-morpho- oil 285.9 91linyl)ethyl]-2-pyridinamine (M + H) + 124 1-(5-bromo-2-pyridinyl)-4-68-69 271.8 91 ethylpiperazine (M + H) + 125 1-(5-bromo-2-pyridinyl)-4-71-72 255.9 91 methylpiperazine (M + H) + 126 4-[(6-bromo-2-pyridinyl)-oil 257.0 84 methyl]morpholine (M + H) + 127 1-[(6-bromo-2-pyridinyl)-oil 283.8 84 methyl]-4-ethylpiperazine (M + H) + 128(4-[(2-bromo-4-pyridinyl)- oil 256.8 84 methyl]morpholine (M + H) + 1291-[(2-bromo-4-pyridinyl)- oil 284.0 84 methyl]-4-ethylpiperazine (M +H) + 130 1-[(2-bromo-4-pyridinyl)- oil 270.2 84methyl]-4-methylpiperazine (M + H) + 131 1-[(6-bromo-2-pyridinyl)- oil270.2 84 methyl]-4-methylpiperazine (M + H) + 1324-[(2-bromo-3-pyridinyl)- oil 256.8 84 methyl]morpholine (M + H) + 1331-[(2-bromo-3-pyridinyl)- oil 283.8 84 methyl]-4-ethylpiperazine (M +H) + 134 1-[(2-bromo-3-pyridinyl)- oil 270.2 84methyl]-4-methylpiperazine (M + H) + 135 1-(5-bromo-2-pyridinyl)-4-(1-110-112 310.3 91 pyrrolidinyl)piperidine (M + H) + 1365-bromo-N-(2-methoxyethyl)- oil 245.1 91 N-methyl-2-pyridinamine (M +H) + 137 5-bromo-2-(1-piperidinyl)- 24-25 241.1 91 pyridine (M + H) +138 2-[4-(5-bromo-2-pyridinyl)-1- 100-102 285.8 91 piperazinyl]ethanol(M + H) + 139 2-[(5-bromo-2-pyridinyl)- 40-42 230.8 91(methyl)amino]ethanol (M + H) + 140 4-(5-bromo-2-pyridinyl)- oil 258.891 thiomorpholine (M + H) + 141 ethyl 1-(5-bromo-2-pyridinyl)- 30-32313.1 91 4-piperidinecarboxylate (M + H) + 1422-{4-[(6-bromo-3-pyridinyl)- 57-59 300.1 84 methyl]-1-piperazinyl}- (M +H) + ethanol 143 6-bromo-3-(1-piperidinyl- 52-54 255.2 84methyl)pyridine (M + H) + 144 1-[(6-bromo-3-pyridinyl)- 87-90 271.1 84methyl]-4-piperidinol (M + H) + 145 4-[(6-bromo-3-pyridinyl)- 88-89273.1 84 methyl]-thiomorpholine (M + H) + 146 4-[(5-bromo-2-pyridinyl)-57-59 257.0 95 methyl]morpholine (M + H) + 147 1-[(5-bromo-2-pyridinyl)-oil 270.03 95 methyl]-4-methylpiperazine (M + H) + 1481-[(5-bromo-2-pyridinyl)- oil 283.98 95 methyl]-4-ethylpiperazine (M +H) + 149 5-bromo-2-(1-piperidinyl- oil 255.2 95 methyl)pyridine (M + H)+

EXAMPLE 14-(4-Chloro-2-fluoroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

4-[(4-Bromo-2-thienyl)methyl]morpholine (prepared according to theprocedure of U.S. Pat. No. 5,866,572) (208.8 mg, 0.80 mmol) wasdissolved in 20 mL of tetrahydrofuran and the solution was cooled to−78° C. Tri-isopropylborate (0.202 mL, 0.80 mmol) was added followed by2.5 M n-butyl lithium in hexane (0.392 mL, 0.98 mmol). The mixture wasstirred at −78° C. for 30 minutes, then allowed to warm to roomtemperature. The solvent was removed in vacuo to providediisopropyl[5-(morpholinomethyl)thien-3-yl]boronate.

A mixture of this boronate,7-bromo-4-(4-chloro-2-fluoroanilino)-3-quinolinecarbonitrile (ReferenceExample 7) (150 mg, 0.40 mmol), tetrakis(triphenylphosphine)palladium(75 mg) and saturated sodium bicarbonate (4 mL) in 7 mL of ethyleneglycol dimethyl ether was heated at 100° C. for 3 hours. The reactionmixture was cooled and treated with 1N sodium hydroxide then extractedwith ethyl acetate. The organic layer was washed with saturated sodiumchloride, dried over sodium sulfate and concentrated in vacuo. Theresidue was triturated with diethyl ether to provide4-(4-chloro-2-fluoroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-yl)-3-quinoline-carbonitrileas a yellow solid;

¹H NMR (DMSO-d₆) δ 2.45-2.60 (m, 6H), 3.50-3.65 (m, 4H), 7.35-7.70 (m,5H), 8.10 (dd, J=8, 4 Hz, 1H), 8.16 (s, 1H), 8.50 (d, J=4 Hz, 1H), 8.59(s, 1H), 9.88 (br s, 1H); MS (ES) m/z 240 (M+2)²⁺, 478.9 (M+1).

EXAMPLE 24-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (250 mg, 0.59 mmol), 4-vinylpyridine (0.10 mL,0.93 mmol), palladium(II)acetate (1.5 mg, 0.007 mmol) andtri-o-tolylphosphine (7 mg, 0.02 mmol) in 3 mL of triethylamine washeated at reflux for 16 hours. Additional triethylamine was added andthe solids were removed by filtration, washing with ethyl acetate,methanol and water. The aqueous and organic layers of the filtrate wereseparated and the aqueous layer was extracted with additional ethylacetate. The organic layers were combined, dried over sodium sulfate,filtered and concentrated in vacuo. The resultant solid was purified byflash silica gel chromatography eluting with 10% methanol in methylenechloride to provide 90 mg (34% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinoline-carbonitrileas a yellow solid, mp 255-257° C.;

¹HNMR (DMSO-d(₆) δ 3.84 (s, 3H), 7.49 (s, 1H), 7.73 (s, 1H), 7.84 (d,J=16 Hz, 1H), 8.12-8.21 (m, 3H), 8.27-8.36 (m, 3H), 8.81-8.90 (m, 3H),9.23 (s, 1H); MS (ES) m/z 447.2 (M+1). Analysis for C₂₄H₁₆Cl₂N₄O-0.7H₂O:Calcd: C, 62.66; H, 3.81; N, 12.18. Found: C, 69.50; H, 3.79; N, 12.28.

EXAMPLE 34-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(2-pyridinyl)ethenyl]-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (250 mg, 0.59 mmol), 2-vinylpyridine (0.10 mL,0.93 mmol), palladium(II)acetate (1.5 mg, 0.007 mmol) andtri-o-tolylphosphine (7 mg, 0.02 mmol) in 5 mL of triethylamine washeated at reflux overnight. The mixture was concentrated in vacuo andthe resultant solid was purified by preparative thin layerchromatography eluting with 10% methanol in methylene chloride toprovide 25 mg (34% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrileas a yellow solid, mp 218-219° C.;

EXAMPLE 44-(2,4-Dichloroanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile

A mixture of 7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile(Reference Example 6) (250 mg, 0.64 mmol), 4-vinylpyridine (0.11 mL,1.02 mmol), palladium(II)acetate (3 mg, 0.015 mmol) andtri-o-tolylphosphine (8 mg, 0.022 mmol) in 5 mL of triethylamine washeated at reflux overnight. The solvent was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The resultant solid was purified by flash silica gelchromatography eluting with ethyl acetate to provide 80 mg (30% yield)of4-(2,4-dichloroanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrileas a yellow solid, mp 240-2429° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 7.55-7.68 (m, 2H), 7.82-7.95 (m,2H), 8.13-8.33 (m, 5H), 8.70 (d, J=9 Hz, 1H), 8.89-8.99 (m, 3H); MS (ES)m/z 417.3 (M+1). Analysis for C₂₃H₁₄Cl₂N₄: Calcd: C, 66.20; H, 3.38; N,13.43. Found: C, 65.90; H, 3.17; N, 13.37.

EXAMPLE 54-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-furyl]-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile(Reference Example 13) (200 mg, 0.42 mmol),tributyl[5-(1,3-dioxolan-2-yl)-2-furanyl]stannane (prepared according tothe procedure of M. Yamamoto, J. Chem. Soc. Chem. Comm., 8, 560 (1988)(220 mg, 0.50 mmol), and a catalytic amount ofdichlorobis(triphenylphosphine)palladium(II) in 5 mL of dioxane washeated at reflux for 4 hours. The mixture was concentrated in vacuo andpartitioned between ethyl acetate and saturated sodium chloride. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated in vacuo to provide 130 mg (64% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-furyl]quinolinecarbonitrile as a yellow solid, mp224-229° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.88 (s, 3H), 4.00-4.04 (m, 2H),4.10-4.15 (m, 2H), 6.04 (s, 1H), 6.82 (d, J=4 Hz, 1H), 7.43 (d, J=4 Hz,1H), 7.54 (s, 1H), 7.86 (s, 1H), 8.19 (s, 1H), 8.24 (d, J=9 Hz, 1H),8.73 (d, J=9 Hz, 1H), 9/09 (s, 1H); MS (ES) m/z 482.3 (M+1). Analysisfor C₂₄H₁₇Cl₂N₃O₄: Calcd: C, 59.77; H, 3.55; N, 8.71. Found: C, 59.70;H, 3.75; N, 8.61.

EXAMPLE 64-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile

A solution of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-furyl]-3quinolinecarbonitrile(Example 5) (90 mg, 0.19 mmol) in 2 mL of tetrahydrofuran and 1 mL of 2Nhydrochloric acid was stirred at room temperature for 4 hours. Themixture was partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic layer was dried over sodium sulfate andfiltered through silica gel. The filtrate was concentrated in vacuo toprovide 40 mg (48% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrileas a yellow solid, mp>250° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.87 (s, 3H), 7.43 (s, 1H), 7.67(d, J=4 Hz, 1H), 7.76 (d, J=4 Hz, 1H), 7.79 (s, 1H), 8.26 (d, J=9 Hz,1H), 8.34 (s, 1H), 8.72 (d, J=9 Hz, 1H), 8.87 (s, 1H), 9.72 (s, 1H); MS(ES) m/z 438.3 (M+1). Analysis for C₂₂H₁₃Cl₂N₃O₃: Calcd: C, 60.29; H,2.99; N, 9.59. Found: C, 60.25; H, 3.12; N, 9.34.

EXAMPLE 77-[5-(4-Morpholinylmethyl)-3-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile

4-[(4-Bromo-2-thienyl)methyl]morpholine (262 mg, 1.0 mmol) was dissolvedin 20 mL of tetrahydrofuran and the solution was cooled to −78° C. 2.5Mn-Butyl lithium in hexane (0.40 mL, 1.0 mmol) was added followed bytri-isopropylborate (209 mg, 1.1 mmol). The mixture was stirred at −78°C. for 30 minutes and then allowed to warm to room temperature. Thesolvent was removed in vacuo to provide the intermediate boronate.

A mixture of this boronate,7-bromo-4-(4-phenoxyanilino)-3-quinolinecarbonitrile (Reference Example10) (208 mg, 0.50 mmol) and tetrakis(triphenylphosphine)palladium(0) (96mg, 0.082 mmol) was heated at reflux in 8.5 mL of ethylene glycoldimethyl ether and 5.1 mL of saturated sodium bicarbonate for 2 hours.The reaction was cooled to room temperature, quenched with 4.1 mL of 1Nsodium hydroxide, and partitioned between ethyl acetate and saturatedsodium chloride. The layers were separated and the ethyl acetate layerwas dried over magnesium sulfate. Removal of the solvent in vacuo gave aresidue which was purified by flash silica gel chromatography elutingwith 5% methanol in methylene chloride to provide 83 mg (32% yield) of7-[5-(4-morpholinylmethyl)-3-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrileas a light tan solid, mp 221-223° C.;

¹H NMR (DMSO-d₆) δ 2.47 (t, J=4 Hz, 4H), 3.61, (t, J=4 Hz, 4H), 3.74 (s,2H), 7.10 (m, 5H), 7.39 (m, 4H), 7.67 (s, 1H), 8.04 (dd, J=10, 2 Hz,1H), 8.17 (dd, J=10, 2 Hz, 2H), 8.51 (d, J=10 Hz, 1H), 8.54 (s, 1H),9.86 (s, 1H); MS (ES) m/z 519.1 (M+1). Analysis for C₃₁H₂₆N₄O₂S-0.25H₂O:Calcd: C, 71.17; H, 5.10; N, 10.71. Found: C, 71.16; H, 4.99; N, 10.51.

EXAMPLE 84-(4-Benzylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

4-[(4-Bromo-2-thienyl)methyl]morpholine (524 mg, 2.0 mmol) was dissolvedin 40 mL of tetrahydrofuran and the solution was cooled to −78° C. 2.5Mn-Butyl lithium in hexane (0.80 mL, 2.0 mmol) was added followed bytri-isopropylborate (418 mg, 2.2 mmol). The mixture was stirred at −78°C. for 30 minutes and then allowed to warm to room temperature. Thesolvent was removed in vacuo to provide the intermediate boronate.

A mixture of this boronate,4-(4-benzylanilino)-7-bromo-3-quinolinecarbonitrile (Reference Example9) (414 mg, 1.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (200mg, 0.17 mmol) was heated it reflux in 15 mL of ethylene glycol dimethylether and 10 mL of saturated sodium bicarbonate for 2 hours. Thereaction was cooled to room temperature, quenched with 8 mL of 1N sodiumhydroxide, and partitioned between ethyl acetate and saturated sodiumchloride. The layers were separated and the ethyl acetate layer wasdried over magnesium sulfate. Removal of the solvent in vacuo gave aresidue which was purified by flash silica gel chromatography elutingwith 5% methanol in methylene chloride to provide 86 mg (17% yield) of4-(4-benzylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrileas a tan solid, mp 228-230° C.; p ¹HNMR(DMSO-d₆) δ 2.46 (t, J=4 Hz, 4H),3.60 (t, J=4 Hz, 4H), 3.74 (s, 2H), 3.99 (s, 2H), 7.25 (m, 9H), 7.66 (s,1H), 8.01 (dd, J=9, 2 Hz, 1H), 8.17 (dd, J=13, 2 Hz, 2H), 8.46 (d, J=9Hz, 1H), 8.55 (s, 1H), 9.91 (s, 1H); MS (ES) m/z 517.1 (M+1). Analysisfor C₃₂H₂₈N₄OS-0.25H₂O: Calcd: C, 73.75; H, 5.41; N, 10.75. Found: C,73.76; H, 5.46; N, 10.78.

EXAMPLE 94-(2,4-Dichloroanilino)-7-{5-[2-(4-morpholinyl)ethyl]-2-thienyl}-3-quinolinecarbonitrile

4-[2-(2-Thienyl)ethyl]morpholine (prepared according to the procedure ofU.S. Pat. No. 5,8665,72) (200 mg, 1.00 mmol) was dissolved in 20 mL oftetrahydrofuran and the solution was cooled to −78° C. 2.5M n-Butyllithium in hexane (0.40 mL, 1.00 mmol) was added and the mixture wasstirred at −78° C. for 30 minutes. Tri-isopropylborate (209 mg, 1.11mmol) was added and the reaction mixture was stirred at −78° C. for 30minutes, then allowed to warm to room temperature. The solvent wasremoved in vacuo to provide the intermediate boronate.

A mixture of the boronate,7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) (200 mg, 0.508 mmol), andtetrakis(triphenylphosphine)palladium(0) (96 mg, 0.082 mmol) was heatedat reflux in 8.4 mL of ethylene glycol dimethyl ether and 5.1 mL ofsaturated sodium bicarbonate for 5 hours. The reaction was quenched with4.1 mL of 1N sodium hydroxide and partitioned between ethyl acetate andsaturated sodium chloride. The layers were separated and the ethylacetate layer was dried over magnesium sulfate. Removal of the solventin vacuo gave a residue which was purified by flash silica gelchromatography eluting with 1:1 ethyl acetate:hexane followed by 3%methanol in methylene chloride. The fractions containing product wereconcentrated and the solid was recrystallized from acetone and hexane toprovide 69 mg (27% yield) of4-(2,4-dichloroanilino)-7-{5-[2-(4-morpholinyl)ethyl]-2-thienyl}-3-quinolinecarbonitrileas a white solid, mp 168-169° C.;

¹H NMR (DMSO-d₆) δ 2.47 (t, J=5 Hz, 4H); 2.61 (t, J=7 Hz, 2H), 3.02 (t,J=7 Hz, 2H), 3.62 (t, J=5 Hz, 4H), 7.00 (d, J=4 Hz, 1H), 7.50-8.51 (m,8H), 9.95 (s, 1H); MS (ES) m/z 511.1 (M+1). Analysis forC₂₆H₂₂Cl₂N₄OS-0.35H₂O: Calcd: C, 60.54; H, 4.42; N, 10.86. Found: C,60.82; H, 4.46; N, 10,38.

EXAMPLE 104-(2,4-Dichloroanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile

1-[(4-Bromo-2-thienyl)methyl]-4-ethylpiperazine (294 mg, 1.08 mmol) wasdissolved in 15 mL of tetrahydrofuran and the solution was cooled to−78° C. Tri-isopropylborate (209 mg, 1.11 mmol) was added followed by2.5 M n-Butyl lithium in hexane (0.40 mL, 1.00 mmol). The mixture wasstirred at −78° C. for 30 minutes and then allowed to warm to roomtemperature. The solvent was removed in vacuo to provide theintermediate boronate.

A mixture of this boronate,7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) (200 mg, 0.509 mmol) andtetrakis(triphenylphosphine)palladium(0) (96 mg, 0.082 mmol) was heatedat reflux in 8 mL of ethylene glycol dimethyl ether and 5 mL ofsaturated sodium bicarbonate for 2 hours. The reaction was cooled toroom temperature, quenched with 4.1 mL of 1.0N sodium hydroxide, andpartitioned between ethyl acetate and saturated sodium chloride. Thelayers were separated and the ethyl acetate layer was dried overmagnesium sulfate. Removal of the solvent in vacuo gave a residue whichwas purified by flash silica gel chromatography eluting with 5% methanolin methylene chloride to provide 180 mg (67% yield) of4-(2,4-dichloroanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrileas a white solid: mp 182-184° C.;

¹H NMR (DMSO-d₆) δ 1.22 (t, J=8 Hz, 3H), 2.50-2.52 (m, 2H), 2.90-3.10(m, 2H), 3.16 (q, J=7 Hz, 2H), 3.40-3.50 (m, 2H), 3.80-4.20 (m, 4H),7.55 (dd, J=9, 2 Hz, 1H), 7.60 (d, J=9 Hz, 1H), 7.72 (s, 1H), 7.83 (d,J=2 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 8.19 (s, 1H), 8.24 (d, J=1 Hz, 1H),8.60 (d, J=9 Hz, 1H), 8.75 (s, 1H); MS (ES) m/z 522.0 (M+1). Analysisfor C₂₇H₂₅Cl₂N₅S-0.2CH₂Cl₂: Calcd: C, 60.55; H, 4.73; N, 12.98. Found:C, 60.43; H, 4.42; N, 12.56.

EXAMPLE 114-(2,4-Dichloroanilino)-7-[5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrile

A solution of 7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile(Reference Example 6) (200 mg, 0.509 mmol) and 4-(4-pentynyl)morpholine(117 mg, 0.763 mmol) in 5 mL of triethylamine was flushed with nitrogenfor 10 minutes. Triphenylphosphine (10.1 mg, 0.039 mmol),copper(I)iodine (2.0 mg, 0.01 mmol) anddichlorobis(triphenylphosphine)palladium(II) (236 mg, 0.039 mmol) wereadded and the resulting mixture was heated at reflux for 12 hours andthen stirred at room temperature overnight. The reaction mixture wasdiluted with triethylamine and filtered. The filtrate was concentratedand the residue was purified by flash silica gel chromatography elutingwith 5% methanol in methylene chloride to provide 25 mg of4-(2,4-dichloroanilino)-7-[5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrileas a off-white solid, mp 131-133° C.;

¹H NMR (DMSO-d₆) δ 1.99 (m, 2H), 2.66 (t, J=7 Hz, 2H), 3.14 (m, 2H),3.26 (t, J=8 Hz, 2H), 3.50 (d, J=11 Hz, 2H), 3.67 (t, J=12 Hz, 2H), 4.02(d, J=11 Hz, 2H), 7.54 (s, 2H), 7.71 (d, J=9 Hz, 1H), 7.80 (s, 1H), 7.92(s, 1H), 8.53 (d, J=9 Hz, 1H), 8.73 (s, 1H), 9.68 (s, 1H); MS (ES) m/z465.4 (M+1).

EXAMPLE 124-(2,4-Dichloroanilino)-7-[(E/Z)-5-(4-morpholinyl)-1-pentenyl]-3-quinolinecarbonitrile

A solution of 7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile(Reference Example 6) (200 mg, 0.509 mmol) and 4-(4-pentenyl)morpholine(118 mag, 0.763 mmol) in 5 mL of dimethylformamide was added to amixture of triphenylphosphine (20 mg, 0.076 mmol), palladium acetate (6mg, 0.025 mmol) and sodium bicarbonate (51 mg, 0.607). The resultingslurry was heated at 120° C. for 4 hours and then stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water and the organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash silica gel chromatography eluting with 5% methanol in methylenechloride to provide 76 mg (32% yield) of4-(2,4-dichloroanilino)-7-[(E/Z)-5-(4-morpholinyl)-1-pentenyl]-3-quinolinecarbonitrileas a white solid: mp 70-72° C.;

¹H NMR (DMSO-d₆) δ 1.85-2.85 (m, 4H), 3.00-3.25 (m, 4H), 3.50-4.00 (m,6H), 5.53-5.86 (m, 1H), 6.70 (m, 1H), 7.52-7.93 (m, 5H), 8.47 (d, J=8Hz, 1H), 8.65 (s, 1H), 9.78 (s, 1H); MS (ES) m/z 467.1 (M+1). Analysisfor C₂₅H₂₄Cl₂N₄O-0.6H₂O: Calcd: C, 62.78; H, 5.30; N, 11.72. Found: C,62.47; H, 5.21; N, 11.48.

EXAMPLE 134-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Product 10,4-(2,4-dichloroanilino-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 4-[(5-bromo-2-furyl)methyl]morpholine in 26% yield, mp118-120° C.;

¹H NMR (DMSO-d₆) δ 2.50 (t, J=5 Hz, 4H), 3.60 (t, J=5 Hz, 4H), 3.63 (s,2H), 6.53 (d, J=3 Hz, 1H), 8.12-8.27 (m, 6H), 8.46-8.60 (m, 2H), 9.93(s, 1H); MS m/z 479.3 (M+1).

EXAMPLE 144-(2,4-Dichloroanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 11,4-(2,4-dichloroanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and propargyl alcohol in 67% yield, mp 251-253° C.;

¹H NMR (DMSO-d₆) δ 4.40 (s, 2H), 7.56 (m, 2H), 7.75 (d, J=9 Hz, 1H),7.83 (d, J=2 Hz, 1H), 7.91 (s, 1H), 8.57 (d, J=9 Hz, 1H), 8.85 (s, 1H);MS (ES) m/z 368.1 (M+1). Analysis for C₁₉H₁₁Cl₂N₃O-0.5CH₂Cl₂: Calcd: C,57.02; H, 2.94; N, 10.23. Found: C, 57.22; H, 2.91; N, 10.34.

EXAMPLE 154-(2,4-Dichloroanilino)-7-[3-(dimethylamino)-1-propynyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 12,4-(2,4-dichloroanilino)-7-[3-(dimethylamino)-1-propynyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 1-dimethylamino-2-propyne in 93% yield, mp 144-145° C.;

¹H NMR (DMSO-d₆) δ 2.29 (s, 6H), 3.55 (s, 2H), 7.49-7.89 (m, 5H),8.40-8.55 (m, 2H), 10.03 (bs, 1H); MS (ES) m/z 395.2 (M+1).

EXAMPLE 164-(2,4-Dichloroanilino)-7-[(E/Z)-6-(4-morpholinyl)-1-hexenyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 12,4-(2,4-dichloroanilino)-7-[(E/Z)-6-(4-morpholinyl)-1-hexenyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 4-(5-hexenyl)morpholine in 13% yield, mp 128-130° C.;

¹H NMR (DMSO-d₆) δ 1.40-1.55 (m, 4H), 2.29-2.84 (m, 6H), 3.45-3.58 (m,6H), 5.45-5.70 (m, 1H), 6.63 (m, 1H), 7.51-7.80 (m, 5H), 8.45-8.55 (m,2H), 9.86 (s, 1H); MS (ES) m/z 481.3 (M+1). Analysis forC₂₆H₂₆Cl₂N₄O-0.3CH₂Cl₂: Calcd: C, 69.30; H, 5.27; N, 11.05. Found: C,62.54; H, 4.95; N, 11.16.

EXAMPLE 177-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 9,7-[4,5-bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloroanilino)-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 4-{[2-(4-morpholinylmethyl)-3-thienyl]methyl}morpholinein 49% yield, mp 118-125° C.;

¹H NMR (DMSO-d₆) δ 2.35-2.45 (m, 8H), 3.62 (s, 4H), 3.70-3.80 (m, 8H),7.53 (d, J=9 Hz, 1H), 7.60 (d, J=9 Hz, 1H), 7.50-7.70 (m, 1H), 7.81 (s,1H), 8.99 (d, J=8 Hz, 1H), 8.06 (s, 1H), 8.53 (d, J=8 Hz, 1H), 8.58 (s,1H), 9.97 (s, 1H); MS (ES) m/z 594.1 (M+1).;

EXAMPLE 184-(2,4-Dichloroanilino)-7-[5-(2-pyridinyl)-2-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloroanilino)-7-[5-(2-pyridinyl)-2-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 2-pyridinyl-2-thiophene in 62% yield, mp 270° C. (dec);

¹H NMR (DMSO-d₆) δ 7.37 (dd, J=5, 3 Hz, 1H), 7.58 (dd, J=7, 2 Hz, 1H),7.64 (d, J=6 Hz, 1H), 7.87 (d, J=2 Hz, 1H), 7.91 (dd, J=7, 2 Hz, 1H),7.96 (s, 2H), 8.05 (d, J=6 Hz, 1H), 8.18 (s, 1H), 8.23 (d, J=7 Hz, 1H),8.60 (d, J=3 Hz, 1H), 8.67 (d, J=7 Hz, 1H), 8.92 (s, 1H); MS (ES) m/z473.1 (M+1). Analysis for C₂₅H₁₄Cl₂N₄S-0.5CH₂Cl₂: Calcd: C, 59.36; H,2.92; N, 10.86. Found: C, 59.03; H, 2.79; N, 10.71.

EXAMPLE 194-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and1-[(4-bromo-2-thienyl)methyl]-4-ethylpiperazine in 26% yield as aoff-white solid, mp 118-120° C.;

¹H NMR (DMSO-d₆) δ 1.21 (t, J=7 Hz, 3H), 2.44-2.55 (m, 2H), 2.95-3.10(m, 2H), 3.16 (q, J=7 Hz, 2H), 3.40-3.51 (m, 4H), 3.87 (s, 3H), 3.92 (s,2H), 7.36 (s, 1H), 7.70 (s, 1H), 7.75 (s, 1H), 8.08 (d, J=9 Hz, 1H),8.17 (s, 1H), 8.20 (s, 1H), 8.56 (d, J=9 Hz, 1H), 8.62 (s, 1H), 9.33 (s,1H); MS (ES) m/z 552.2 (M+1). Analysis for C₂₈H₂₇Cl₂N₅OS-0.25CH₂Cl₂:Calcd: C, 59.08; H, 4.82; N, 12.21. Found: C, 58.96; H, 4.72; N, 11.98.

EXAMPLE 207-[4,5-bis(4-Morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 9,7-[4,5-bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and4-{[2-(4-morpholinylmethyl)-3-thienyl]methyl}morpholine in 53% yield asa light yellow solid, mp 118-125° C.;

¹H NMR (DMSO-d₆) δ 2.35-2.45 (m, 4H), 3.25-3.35 (m, 4H), 3.55-3.65 (m,8H), 3.73 (s, 3H), 3.86 (s, 4H), 7.41 (s, 1H), 7.64 (s, 1H), 7.76 (s,1H), 7.95-8.10 (m, 2H), 8.45-8.60 (m, 2H), 10.00 (s, 1H); MS (ES) m/z624.0 (M+1). Analysis for C₃₁H₃₁Cl₂N₅O₃S-0.7CH₂Cl₂: Calcd: C, 55.65; H,4.76; N, 9.84. Found: C, 55.64; H, 4.61; N, 9.52.

EXAMPLE 214-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(E)-3-(4-morpholinyl)-1-propenyl]-2-thienyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 9,4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(E)-(4-morpholinyl)-1-propenyl]-2-thienyl}-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(E)-3-(2-thienyl)-2-propenyl]morpholine in20% yield, mp) 145° C. (dec);

¹H NMR (DMSO-d₆) δ 3.00-3.25 (m, 4H), 3.50-3.75 (m, 4H), 3.86 (s, 3H),3.96 (d, J=7 Hz, 2H), 6.16 (dd, J=16, 7 Hz, 1H), 7.08 (d, J=16 Hz, 1H),7.30-7.40 (m, 2H), 7.73 (s, 1H), 7.83 (d, J=3 Hz, 1H), 7.95-8.20 (m,2H), 8.50-8.70 (m, 2H), 9.96 (bs, 1H); MS (ES) m/z 551.1 (M+1). Analysisfor C₂₈H₂₄Cl₂N₄O₂S-2.0H₂O: Calcd: C, 59.23; H, 4.78; N, 9.50. Found: C,59.59; H, 4.59; N, 9.00.

EXAMPLE 224-(2,4-Dichloro-5-methoxyanilino)-7-{5-[4-(4-morpholinyl)butyl]-2-thienyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 9,4-(2,4-dichloro-5-methoxyanilino)-7-{5-[4-(4-morpholinyl)butyl]-2-thienyl}-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[4-(2-thienyl)butyl]-morpholine in 51%yield, mp 188° C. (dec);

¹H NMR (DMSO-d₆) δ 1.50 (m, 2H), 1.70 (m, 2H), 2.25-2.40 (m, 4H), 2.87(t, J=7 Hz, 2H), 3.30-3.50 (m, 4H), 3.56 (t, J=5 Hz, 2H), 3.86 (s, 3H),6.96 (d, J=4 Hz, 1H), 7.20-7.45 (m, 1H), 7.55-7.80 (m, 3H), 7.81-8.12(m, 2H), 8.40-8.60 (m, 1H), 10.01 (br s, 1H); MS (ES) m/z 567.3 (M+1).Analysis for C₂₀H₂₈Cl₂N₄O₂S-0.25H₂O: Calcd: C, 60.89; H, 5.01; N, 9.80.Found: C, 60.46; H, 4.97; N, 9.87.

EXAMPLE 234-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(5-bromo-2-thienyl)methyl]morpholine in 24%yield, mp 188° C.;

¹H NMR (DMSO-d₆) δ 2.30-2.55 (m, 4H), 3.40-3.75 (m, 6H), 3.86 (s, 3H),7.05-8.50 (m, 8H), 10.03 (s, 1H); MS (ES) m/z 525.2 (M+1). Analysis forC₂₆H₂₂Cl₂N₄O₂S-0.17CH₂Cl₂-0.17EtOAc: Calcd: C, 58.14; H, 4.29; N, 10.11.Found: C, 58.28; H, 4.06; N, 9.68.

EXAMPLE 244-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(4-bromo-2-thienyl)methyl]morpholine in41%, yield; mp, 216-217° C.;

¹H NMR (DMSO-d₆) δ 2.35-2.50 (m, 4H), 3.55-3.65 (m, 4H), 3.75 (s, 2H),3.87 (s, 3H), 7.42 (s, 1H), 7.68 (s, 1H), 7.77 (s, 1H), 8.08 (d, J=9 Hz,1H), 8.17 (s, 1H), 8.22 (s, 1H), 8.54 (d, J=9 Hz, 1H), 8.57 (s, 1H),9.99 (s, 1H); MS (ES) m/z 525.2 (M+1). Analysis for C₂₆H₂₂Cl₂N₄O₂S:Calcd: C, 59.43; H, 4.22; N, 10.66. Found: C, 59.28; H, 3.93; N, 10.61.

EXAMPLE 254-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) and 4-[(4-bromo-2-thienyl)methyl]morpholine in 66% yield, mp203-205° C.;

¹H NMR (DMSO-d₆) δ 2.35-2.45 (m, 4H), 3.60 (t, J=4 Hz, 4H), 3.75 (s,2H), 7.50-7.62 (m, 2H), 7.67 (s, 1H), 7.80 (s, 1H), 8.09 (d, J=8 Hz,1H), 8.16 (s, 1H), 8.21 (s, 1H), 8.52 (d, J=8 Hz, 1H), 8.57 (s, 1H),9.92 (s, 1H); MS (ES) m/z 495.3 (M+1). Analysis forC₂₅H₂₀Cl₂N₄OS-0.5EtOAc: Calcd: C, 60.11; H, 4.47; N, 10.38. Found: C,60.27; H, 4.48; N, 10.37.

EXAMPLE 264-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

To a dry flask under a nitrogen atmosphere was added 200 mg (0.78 mmol)of 4-(3-bromobenzyl)morpholine, 0.218 g (0.86 mmol) ofbis(pinacolato)diboron, 230 mg (2.34 mmol) of potassium acetate, 5 mL ofdimethylsulfoxide and 32 mg (0.04 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane. The reaction mixture was heated at 80° C. for 2 hours.After cooling, the mixture was partitioned between 20 mL of toluene, 40mL of ethyl acetate and 40 mL of water. The layers were separated andthe aqueous layer was further extracted with 30 mL of ethyl acetate. Theorganic layers were combined and washed with 4×40 mL water. After dryingover magnesium sulfate, removal of the solvents gave crude4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine as adark oil.

A mixture of 110 mg (0.26 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8), crude4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine and45 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium(0) was heatedat reflux in 4 mL of ethylene glycol dimethyl ether and 2.5 mL ofsaturated aqueous sodium bicarbonate for 2 hours. After cooling, themixture was partitioned between 50 mL of ethyl acetate and 40 ml ofwater. The layers were separated and the ethyl acetate layer was driedover magnesium sulfate. Removal of the solvent in vacuo gave a darkresidue which was purified by flash silica gel chromatography elutingwith a gradient of ethyl acetate to 95:5 ethyl acetate/methanol), toprovide 70 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinoline-carbonitrileas a yellow solid, mp 88-91° C.;

¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 8.61 (broad s, 2H), 8.19 (s, 1H),8.08-7.97 (m, 1H), 7.85-7.72 (m, 3H), 7.51 (m, J=8 Hz, 1H), 7.43 (s,1H), 7.41 (s, 1H), 3.87 (s, 3H), 3.61 (s, 2H), 3.59 (s, 4H), 2.42 (s,4H); MS (ES) m/z 519.1, 521.0 (M+1). Analysis forC₂₈H₂₄Cl₂N₄O₂.0.5EtOAc: Calcd: C, 63.95; H, 5.01; N, 9.94. Found: C,63.64; H, 4.93; N, 9.97.

EXAMPLE 274-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 800 mg (2.52 mmol) of 4-[2-(4-iodophenyl)ethyl]morpholinewas reacted with 704 mg (2.77 mmol) of bis(pinacolato)diboron, 743 mg(7.57 mmol) of potassium acetate and 103 mg, (0.13 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 15 mL of anhydrous dimethylsulfoxide to providecrude4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl]morpholine.

By the procedure of Example 26, 266 mg (0.63 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with crude4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl]morpholineand 218 mg (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7mL of ethylene glycol dimethyl ether and 4 mL of saturated aqueoussodium bicarbonate to provide 230 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrileas a yellow solid after purification, mp>170° C. (dec);

¹H NMR (DMSO-d₆) δ 10.03 (s, 1H), 8.60 (m, 2H), 8.19 (s, 1H), 8.10-8.03(m, 1H), 7.87-7.75 (m, 3H), 7.43-7.39 (m, 3H), 3.87 (s, 3H), 3.59 (m,4H), 2.83 (t, J=7 Hz, 2H), 2.60-2.53 (m, 2H), 2.46 (broad s, 4H); MS(ES) m/z 533.1, 535.1 (M+1). Analysis for C₂₉H₂₆Cl₂N₄O₂.0.4 MeOH: Calcd:C, 64.64; H, 5.09; N, 10.26. Found: C, 64.73; H, 5.00; N, 9.86.

EXAMPLE 284-(2,4-Dichloro-5-methoxyanilino)-7-{3-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine, inExample 26, 1.0 g (3.70 mmol) of 4-(3-bromophenethyl)morpholine, wasreacted with 1.03 g (4.07 mmol) of bis(pinacolato)diboron, 1.1 g (11.0mm of potassium acetate and 0.3 g (0.37 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 25 mL of anhydrous dimethylsulfoxide to providecrude4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl]morpholine.This material was purified by flash silica gel chromatography, elutingwith a gradient of 99:1 methylene chloride/methanol to 97.5:2.5methylene chloride/methanol, to provide 0.52 g of4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine as alight brown liquid; MS (ES) m/z 318.3 (M+1).

By the procedure for Example 26, 107 mg (0.25 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with 0.160 g (0.50 mmol) of4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine and57 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) in 6 mL ofethylene glycol dimethyl ether and 2.5 mL of saturated aqueous sodiumbicarbonate to provide 115 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{3-[2-(4-morpholinyl)ethyl]phenyl}3-quinolinecarbonitrileas a yellow solid after purification, mp 146-148° C.;

¹H NMR (DMSO-d₆) δ 10.05 (s, 1H), 8.62 (broad s, 2H), 8.22 (m , 1H),8.07-8.01 (m, 1H), 7.81-7.71 (m, 3H), 7.50-7.32 (m, 3H), 3.87 (s, 3H),3.60 (broad s, 4H), 2.92-2.83 (m, 2H), 2.67-2.56 (m, 2H), 2.50 (broad s,4H); MS (ES) m/z 533.1, 535.1 (M+1). Analysis forC₂₉H₂₆Cl₂N₄O₂.0.5EtOAc.0.15CH₂Cl₂: Calcd: C, 63.38; H, 5.17; N, 9.49.Found: C, 63.54; H, 5.03; N, 9.31.

EXAMPLE 294-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 500 mg (1.95 mmol) of 4-(4-bromobenzyl)morpholine wasreacted with 545 mg (2.15 mmol) of bis(pinacolato)diboron, 575 mg (5.86mmol) of potassium acetate and 80 mg (0.098 mmol) of[1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 10 mL of anhydrous dimethylsulfoxide to providecrude4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine.

By the procedure for Example 26, 247 mg (0.59 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with crude4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine and150 mg (0.13 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7 mLof ethylene glycol dimethyl ether and 4 ml of saturated aqueous sodiumbicarbonate to provide 180 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrileas a yellow solid after purification, mp>180° C. (dec);

¹H NMR (DMSO-d₆) δ 10.03 (s, 1H), 8.60 (broad s, 2H), 8.20 (s, 1H),8.08-8.00 (m, 1H), 7.92-7.84 (m, 2H), 7.76 (s, 1H), 7.50 (s, 1H), 7.47(s, 1H), 7.42 (s, 1H), 3.87 (s, 3H), 3.60 (t, J=4.5 Hz, 4H), 3.54 (s,2H), 2.42-2.38 (m, 4H); MS (ES) m/z 519.2, 521.2 (M+1). Analysis forC₂₈H₂₄Cl₂N₄O₂.0.4H₂O: Calcd: C, 63.86; H, 4.75; N, 10.64. Found: C,64.15; H, 4.57; N, 10.26.

EXAMPLE 304-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 800 mg (2.82 mmol) of 1-(4-bromobenzyl)-4-ethylpiperazine,was reacted with 789 mg (3.11 mmol) of bis(pinacolato)diboron, 832 mg(8.47 mmol) of potassium acetate and 115 mg (0.14 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 15 mL of anhydrous dimethylsulfoxide to providecrude1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine.This material was divided into two equal portions, one of which was usedin the subsequent step).

By the procedure of Example 26, 179 mg (0.42 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with crude1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazineand 147 mg (0.13 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7mL of ethylene glycol dimethyl ether and 4 mL of saturated aqueoussodium bicarbonate to provide 70 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrileas a yellow solid after purification, mp>155° C. (dec);

¹H NMR (DMSO-d₆) δ 10.04 (broad s, 1H), 8.56 (broad s, 2H), 8.20-8.18(m, 1H), 8.05-7.93 (m, 1H), 7.88-7.79 (m, 2H), 7.77-7.68 (m, 1H), 7.48(s, 1H), 7.45 (s, 1H), 7.39-7.35 (m, 1H), 3.86 (s, 3H), 3.54 (s, 2H),2.50-2.31 (m, 10H), 1.00 (t, J=7 Hz, 3H); MS (ES) m/z 546.1, 548.1(M+1). Analysis for C₃₀H₂₉Cl₂N₅O.1.0MeOH.0.94H₂O: Calcd: C, 62.53; H,5.90; N, 11.76. Found: C, 62.33; H, 5.50; N, 11.36.

EXAMPLE 314-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-6-methoxy-3-quinolinecarbonitrile

By the procedure for Example 26, 221 mg (0.59 mmol) of3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was reacted with halfof the crude1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazineintermediate generated for the synthesis of Example 30 and 147 mg (0.13)mmol) of tetrakis(triphenylphosphine)palladium(0) in 7 mL of ethyleneglycol dimethyl ether and 4 mL of saturated aqueous sodium bicarbonateto provide 85 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]-phenyl}-6-methoxy-3-quinolinecarbonitrileas a yellow solid after purification, mp 126-130° C.;

¹H NMR (DMSO-d₆) δ 9.86 (broad s, 1H), 8.45 (s, 1H), 7.97 (s, 1H),7.82-7.73 (m, 3H), 7.58 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz, 2H), 3.95 (s,3H), 3.88 (s, 3H), 3.52 (s, 2H), 2.50-2.28 (m, 8H), 2.32 (q, J=7 Hz,2H), 0.99 (t, J=7 Hz, 3H); MS (ES) m/z 576.1, 578.0 (M+1). Analysis forC₃₁H₃₁Cl₂N₅O₂.0.75H₂O: Calcd: C, 63.10; H, 5.54; N, 11.85. Found: C,63.50; H, 5.74; N, 11.47.

EXAMPLE 324-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-ethyl-1-piperazinyl)ethyl])phenyl}-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 800 mg (2.32 mmol) of1-ethyl-4-[2-(4-iodophenyl)ethyl]piperazine, was reacted with 649 mg(2.56 mmol) of bis(pinacolato)diboron, 684 mg (6.87 mmol) of potassiumacetate and 95 mg (0.12 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 15 mL of anhydrous dimethylsulfoxide to providecrude1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl]piperazine.This material was divided into two equal portions, one of which was usedin the subsequent step.

By the procedure of Example 26, 147 mg (0.35 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with crude1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenethyl]piperazineand 121 mg (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7mL of ethylene glycol dimethyl ether and 4 mL of saturated aqueoussodium bicarbonate to provide 48 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[2-(4-ethyl-1-piperazinyl)ethyl]phenyl}-3-3-quinolinecarbonitrileas a yellow solid after purification, mp 75-78° C.;

¹H NMR (DMSO-d₆) δ 10.25-9.85 (broad s, 1H), 8.54 (broad s, 2H), 8.09(s, 1H), 8.00-7.92 (m, 1H), 7.85-7.75 (m, 3H), 7.71 (s, 1H), 7.42 (s,1H), 7.40 (s, 1H), 3.86 (s, 3H), 2.81 (t, J=7 Hz, 2H), 2.55 (t, J=7 Hz,2H), 2.51-2.25 (m, 10H), 0.99 (t, J=7 Hz, 3H); MS (ES) m/z 533.1, 535.1(M+1). Analysis for C₃₁H₃₁Cl₂N₅O.1.0EtOAc: Calcd: C, 64.81; H, 6.06; N,10.80. Found: C, 64.55; H, 5.95; N, 10.86.

EXAMPLE 334-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 400 mg (1.53 mmol) of4-[(4-bromo-2-thienyl)methyl]morpholine was reacted with 426 mg (1.68mmol) of bis(pinacolato)diboron, 449 mg (4.58 mmol) of potassium acetateand 62 mg (0.076 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 7 mL of anhydrous dimethylsulfoxide to providecrude4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}morpholine.

By the procedure of Example 26, 215 mg (0.63 mmol) of7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(Reference Example 14) was reacted with crude4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}morpholineand 159 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7mL of ethylene glycol dimethyl ether and 4 mL of saturated aqueoussodium bicarbonate to provide 104 mg of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrileas a yellow solid after purification, mp 110-113° C.;

¹H NMR (DMSO-d₆) δ 9.89 (s, 1H), 8.64 (s, 1H), 8.41 (d, J=10 Hz, 1H),8.22 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.55 (d,J=1 Hz, 1H); 7.48 (d, J=2 Hz, 1H), 7.20 (dd, J=9, 2 Hz, 1H), 7.17 (d,J=1 Hz, 1H), 6.55 (d, J=9 Hz, 1H), 3.74 (s, 2H), 3.61 (s, 3H), 3.60 (t,J=5 Hz, 4H), 2.45 (t, J=4 Hz, 4H); MS (ES) m/z 573.3, 575.3 (M+1).Analysis for C₂₉H₂₅ClN₆OS_(2.0.25)CH₂Cl₂: Calcd: C, 59.01; H, 4.32; N,14.14. Found: C, 59.32; H, 4.32; N, 13.75.

EXAMPLE 347-[3,4-bis(4-Morpholinylmethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

By the procedure used to prepare4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine inExample 26, 800 mg (2.25 mmol) of4-[4-bromo-2-(4-morpholinylmethyl)benzyl]morpholine was reacted with 629mg (2.48 mmol) of bis(pinacolato)diboron, 663 mg (6.75 mmol) ofpotassium acetate and 115 mg (0.14 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane in 15 mL of anhydrous dimethylsulfoxide to providecrude4-[2-(4-morpholinylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine.This material was divided into two equal portions, one of which was usedin the subsequent step.

By the procedure of Example 26, 143 mg (0.34 mmol) of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) was reacted with crude4-[2-(4-morpholinylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholineand 117 mg (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) in 5mL of ethylene glycol dimethyl ether and 3 mL of saturated aqueoussodium bicarbonate to provide 105 mg of7-[3,4-bis(4-morpholinylmethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrileas a yellow solid after purification, mp 198-00° C.;

¹H NMR (DMSO-d₆) δ 10.04 (s, 1H), 8.60 (broad s, 2H), 8.18 (s, 1H),8.08-8.98 (m, 1H), 7.85-7.74 (m, 3H), 7.48 (d, J=8 Hz, 1H), 7.42 (s,1H), 3.86 (s, 3H), 3.69 (s, 2H), 3.66 (s, 2H), 3.58 (broad s, 8H),2.46-2.38 (m, 8H); MS (ES) m/z 618.2, 620.2 (M+1). Analysis forC₃₃H₃₃Cl₂N₅O₃: Calcd: C, 64.08; H, 5.38; N, 11.32. Found: C, 63.91; H,5.56; N, 11.02.

EXAMPLE 357-[3,4-bis(4-Morpholinylmethyl)phenyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile

By the procedure for Example 26, 221 mg (0.59 mmol) of7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(Reference Example 14) was reacted with half of the crude4-[2-(4-morpholinylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholineintermediate generated for the synthesis of Example 34 and 117 mg (0.10mmol) of tetrakis(triphenylphosphine)palladium(0) in 5 mL of ethyleneglycol dimethyl ether and 3 mL of saturated aqueous sodium bicarbonateto provide 90 mg of7-[3,4-bis(4-morpholinylmethyl)phenyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrileas a yellow solid after purification, mp>25° C. (dec);

¹H NMR (DMSO-d₆): δ 9.95 (s, 1H), 8.67 (s, 1H), 8.48 (d, J=9 Hz, 1H),8.20 (s, 1H), 8.02 (d, J=9 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J=8 Hz, 1H),7.55 (s, 1H), 7.50-7.46 (m, 2H), 7.21 (dd, J=8, 2 Hz, 1H), 7.17 (s, 1H),6.56 (d, J=9 Hz, 1H), 3.69 (s, 2H), 3.66 (s, 2H), 3.62 (s, 3H), 3.58(broad s, 8H), 2.41 (broad s, 8H); MS (ES) m/z 666.2, 668.2 (M+1).Analysis for C₃₆H₃₆ClN₇O₂S.0.25CH₂Cl₂: Calcd: C, 63.33; H, 5.35; N,14.26. Found: C, 63.19; H, 5.60; N, 13.87.

EXAMPLE 364-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 24,3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was converted to4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[5-(4-morpholinyl-methyl)-3-thienyl]-3-quinolinecarbonitrilein 47% yield, mp 148-150° C.;

¹H NMR (DMSO-d₆) δ 9.87 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.97 (s,2H), 7.79 (s, 1H), 7.40 (s, 1H), 4.69 (s, 3H), 3.88 (s, 3H), 3.61 (s,2H), 3.47 (m, 4H), 2.50 (m, 4H); MS (ES) m/z 556.4 (M+1). Analysis forC₂₇H₂₄Cl₂N₄O₃S-1.3H₂O: Calcd: C, 56.01; H, 4.27; N, 9.66. Found: C,55.67; H, 4.27; N, 9.65.

EXAMPLE 374-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 29,3-cyano-4(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was converted to4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[4-(4-morpholinyl-methyl)phenyl]-3-quinolinecarbonitrilein 42% yield, mp 108-110° C.;

¹H NMR (DMSO-d₆) δ 9.85 (s, 1H), 8.47 (s, 1H), 7.90 (s, 1H), 7.83 (s,1H), 7.78 (s, 1H), 7.60 (d, J=8 Hz, 2H), 7.43 (d, J=10 Hz, 3H), 3.96 (s,3H), 3.88 (s, 3H), 3.61 (t, J=4 Hz, 4H), 3.52 (s, 2H), 2.40 (br s, 4H);MS (ES) m/z 549.1 (M+1). Analysis for C₂₉H₂₆Cl₂N₄O₃-0.7H₂O: Calcd: C,61.94; H, 4.92; N, 9.95. Found: C, 61.95; H, 4.96; N, 9.63.

EXAMPLE 384-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{3-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 28,3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was converted to4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-{3-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrilein 45% yield, mp 193-195° C.;

¹H NMR (DMSO-d₆) δ 9.85 (s, 1H), 8.47 (s, 1H), 7.97 (s, 1H), 7.82 (s,1H), 7.78 (s, 1H), 7.47 (m, 3H), 7.30 (s, 1H), 7.27 (s, 1H), 3.95 (s,3H), 3.88 (s, 3H), 3.60 (t, J=4 Hz, 4H), 3.52 (t, J=6 Hz, 2H), 2.59 (t,J=8 Hz, 2H), 2.40 (br s, 4H); MS (ES) m/z 563.1 (M+1). Analysis forC₂₉H₂₆Cl₂N₄O₃-0.98H₂O: Calcd: C, 61.98; H, 5.20; N, 9.62. Found: C,61.98; H, 4.95; N, 9.24.

EXAMPLE 394-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinylmethyl]phenyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 26,3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was converted to4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinylmethyl]phenyl}-3-quinolinecarbonitrilein 59% yield, mp 155-158° C.;

¹H NMR (DMSO-d₆) δ 9.88 (s, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.83 (s,1H), 7.79 (s, 1H), 7.55 (m, 5H), 3.95 (s, 3H), 3.88 (s, 3H), 3.61 (t,J=4 Hz, 4H), 3.58 (s, 2H), 2.40 (br s, 4H); MS (ES) m/z 549.1 (M+1).Analysis for C₂₉H₂₆Cl₂N₄O₃-0.2H₂O: Calcd: C, 62.97; H, 4.82; N, 9.91.Found: C, 63.01; H, 4.87; N, 9.52.

EXAMPLE 404-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 27,3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) was converted to4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrilein 40% yield, mp 215-217° C.;

¹H NMR (DMSO-d₆) δ 9.86 (s, 1H), 8.47 (s, 1H), 7.97 (s, 1H), 7.81 (d,J=8 Hz, 2H), 7.55 (d, J=7 Hz, 2H), 7.40 (s, 1H), 7.35 (s, 1H), 7.33 (s,1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.61 (t, J=4 Hz, 4H), 2.89 (t, J=7 Hz,2H), 2.59 (t, J=7 Hz, 2H), 2.46 (s, 4H); MS (ES) m/z 563.1 (M+1).Analysis for C₂₉H₂₆Cl₂N₄O₃-0.6H₂O: Calcd: C, 62.60; H, 5.13; N, 9.49.Found: C, 62.70; H, 5.00; N, 9.12.

EXAMPLE 414-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile

N-Methylpiperazine (0.065 mL, 0.56 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.45 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (500 mg, 2.36 mmol) was added. Afterstirring at 0° C. for 1 hour, a catalytic amount of acetic acid wasadded and the reaction mixture was allowed to warm to room temperature.The reaction was quenched by the addition of water and then partitionedbetween saturated sodium bicarbonate and methylene chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography eluting with agradient of 10% methanol in methylene chloride to 20% methanol inmethylene chloride to provide 95 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile(40% yield) mp 157-160° C.; MS (ES) m/z 522.3 (M+1). Analysis forC₂₇H₂₅Cl₂N₅O₂-0.9H₂O: Calcd: C, 60.20; H, 5.01; N, 13.00. Found: C,60.05; H, 4.62; N, 13.00.

EXAMPLE 424-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile(Reference Example 13) (2.50 g, 5.32 mmol),tributyl[5-(1,3-dioxolan-2-yl)-3-thienyl]stannane (2.98 g, 6.69 mmol),and a catalytic amount of dichlorobis(triphenylphosphine)palladium(II)in 60 mL of dioxane was heated at reflux for 4.5 hours. The mixture wasconcentrated in vacuo and partitioned between ethyl acetate andsaturated sodium chloride. The organic layer was dried over sodiumsulfate and concentrated in vacuo. A 300 mg portion was removed andtriturated with ethyl acetate to provide 104 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-3-quinoline-carbonitrileas a yellow solid, mp 234-236° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.88 (s, 3H), 3.80-4.12 (m, 4H),6.15 (s, 1H), 7.57 (s, 1H), 7.87 (s, 2H), 8.23 (s, 1H), 8.31 (d, J=9 Hz,1H), 8.36 (s, 1H), 8.76 (d, J=9 Hz, 1H), 9.13 (s, 1H); MS (ES) m/z498.1, 500.1 (M+1). Analysis for C₂₄H₁₇Cl₂N₃O₃S-0.25H₂O: Calcd: C,57.32; H, 3.51; N, 8.36. Found: C, 57.41; H, 3.26; N, 8.48.

EXAMPLE 434-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile

A solution of crude4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-3-quinolinecarbonitrile(Example 42) in 100 mL of tetrahydrofuran and 50 mL of 2N hydrochloricacid was stirred at room temperature overnight. Saturated sodiumbicarbonate was slowly added and the product was extracted into ethylacetate. The organic layer was washed with saturated sodium chloride,dried over magnesium sulfate, filtered and concentrated in vacuo. Ethylacetate was added and the solid collected to provide 1.296 g of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrileas a yellow solid, mp 259-262° C. (dec);

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.88 (s, 3H), 7.51 (s, 1H), 7.89(s, 1H), 8.30 (s, 1H), 8.39 (d, J=9 Hz, 1H), 8.67 (s, 1H), 8.80-8.88 (m,2H), 9.20 (s, 1H), 10.06 (s, 1H); MS (ES) m/z 454.1, 456.1 (M+1).Analysis for C₂₂H₁₃Cl₂N₃O₂S: Calcd: C, 58.16; H, 2.88; N, 9.25. Found:C, 57.93; H, 2.87; N, 9.22.

EXAMPLE 444-(2,4-Dichloroanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile

Following the procedures in Examples 42 and 43,7-bromo-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile (ReferenceExample 6) (370 mg, 0.94 mmol) was converted to 204 mg of4-(2,4-dichloroanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrileas a yellow solid, mp 286-288° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 7.63 (dd, J=7, 2 Hz, 1H), 7.74(d, J=7 Hz, 1H), 7.92 (d, J=2 Hz, 1H), 8.06 (d, J=3 Hz, 1H), 8.14 (d,J=3 Hz, 1H), 8.31 (d, J=2 Hz, 1H), 8.40 (dd, J=7, 2 Hz, 1H), 8.82 (d,J=7 Hz, 1H), 9.24 (s, 1H), 10.00 (s, 1H); MS (ES) m/z 424.2, 426.2(M+1). Analysis for C₂₁H₁₁Cl₂N₃OS: Calcd: C, 59.45; H, 2.61; N, 9.90.Found: C, 59.14; H, 2.50; N, 9.72.

EXAMPLE 454-(2,4-Dichloro-5-methoxyanilino)-6-(5-formyl-3-thienyl)-3-quinolinecarbonitrile

Following the procedures in Examples 42 and 43,6-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 3) (226 mg, 0.53 mmol) was converted to 212 mg of4-(2,4-dichloro-5-methoxyanilino)-6-(5-formyl-3-thienyl)-3-quinolinecarbonitrileas a yellow solid, mp 233-237° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.88 (s, 3H), 7.58 (s, 1H), 7.89(s, 1H), 8.08 (d, J=9 Hz, 1H), 8.52 (d, J=9 Hz, 1H), 8.65 (s, 1H), 8.72(s, 1H), 9.04-9.14 (m, 2H), 10.03 (s, 1H); MS (ES) m/z 454.1, 456.1(M+1). Analysis for C₂₂H₁₃Cl₂N₃O₂S: Calcd: C, 58.16; H, 2.88; N, 9.25.Found: C, 57.77; H, 2.90; N, 8.87.

EXAMPLE 464-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile

N-Methylpiperazine (0.080 mL, 0.72 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile(Example 43) (220 mg, 0.48 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (500 mg, 2.36 mmol) was added followed by adrop of acetic acid. After stirring at 0° C. for 10 minutes the ice bathwas removed and the reaction mixture was stirred at room temperature for3 hours. The reaction was quenched by the addition of water and thenpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography eluting with a gradient of 20% methanol in methylenechloride to 30% methanol in methylene chloride to provide 152 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile(59% yield) as a white solid, mp 206-209° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 2.88 (s, 3H), 3.08-3.70 (br m,8H), 3.88 (s, 3H), 4.48 (s, 2H), 7.58 (s, 1H), 7.85 (s, 1H), 7.88 (s,1H), 8.24 (s, 1H), 8.30 (d, J=8 Hz, 1H), 8.43 (s, 1H), 8.80 (d, J=8 Hz,1H), 9.20 (s, 1H); MS (ES) m/z 538.2, 540.2 (M+1). Analysis forC₂₇H₂₅Cl₂N₅OS: Calcd: C, 60.22; H, 4.68; N, 13.01. Found: C, 59.85; H,4.60; N, 13.23.

EXAMPLE 47(2R)-1-({5-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-furyl}methyl)-2-pyrrolidinecarboxamide

Prolinamide (77.0 mg, 0.67 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (245 mg, 0.56 mmol) in 3 ml of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (620 mg, 2.93 mmol) was added. Afterstirring at 0° C. for 1 hour, a catalytic amount of acetic acid wasadded and the reaction mixture was slowly allowed to warm to roomtemperature. The reaction was quenched by the addition of saturatedsodium bicarbonate and extracted with methylene chloride. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash column chromatography eluting with 10% methanol in methylenechloride to provide 210 mg of(2R)-1-({5-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-furyl}methyl)-2-pyrrolidinecarboxamide(70% yield) as a yellow solid, mp 121-126° C.; MS (ES) m/z 536.1 (M+1).Analysis for C₂₇H₂₃Cl₂N₅O₃-1.0H₂O: Calcd: C, 58.49; H, 4.55; N, 12.63.Found: C, 58.77; H, 4.42; N, 12.43.

EXAMPLE 487-[5-(4-Morpholinylmethyl)-3-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile

4-[(5-Bromo-3-pyridinyl)methyl]morpholine (277 mg, 1.08 mmol) wasdissolved in 15 mL of tetrahydrofuran and the solution was cooled to−78° C. 2.5M n-Butyl lithium in hexane (0.42 mL, 1.05 mmol) was addedfollowed by tri-isopropylborate (209 mg, 1.11 mmol). The mixture wasstirred at −78° C. for 30 min and then allowed to warm to roomtemperature. The solvent was removed in vacuo to provide theintermediate boronate. A mixture of this boronate,7-bromo-4-(4-phenoxyanilino)-3-quinolinecarbonitrile (Reference Example10)(250 mg, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (96mg, 0.082 mmol) was heated at reflux in 8.0 mL of ethylene glycoldimethyl ether and 5.0 mL of saturated sodium bicarbonate for 2 hours.The reaction was cooled to room temperature, quenched with 4.1 mL of 1Nsodium hydroxide, and partitioned between ethyl acetate and brine. Thelayers were separated and the ethyl acetate layer was dried overmagnesium sulfate. Removal of the solvent in vacuo gave a residue whichwas purified by flash silica gel chromatography eluting with a gradientof ethyl acetate to 5% methanol in ethyl acetate to provide 102 mg (33%yield) of7-[5-(4-morpholinylmethyl)-3-pyridinyl]-4-(phenoxyanilino)-3-quinolinecarbonitrileas a yellow solid: mp 185-187° C.;

¹H NMR (DMSO-d₆): δ 2.43 (t, J=4 Hz, 4H), 3.60 (t, J=4 Hz, 4H), 3.63 (s,2H), 7.05 (dd, J=9, 1 Hz, 2H), 7.13 (m, 3H), 7.40 (m, 4H), 8.07 (dd,J=9, 2 Hz, 1H), 8.21 (s, 1H), 8.26 (s, 1H), 8.61 (m, 3H), 9.01 (d, J=2Hz, 1H), 9.97 (s, 1H); MS (ES) m/z 514.2 (M+1). Analysis forC₃₂H₂₇N₅O₂-0.5H₂O; Calcd: C, 73.55; H, 5.40; N, 13.40. Found: C, 73.64;H, 5.41; N, 13.31.

EXAMPLE 494-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile

4-[(5-Bromo-3-pyridinyl)methyl]morpholine (977 mg, 1.08 mmol) wasdissolved in 15 mL of tetrahydrofuran and the solution was cooled to−78° C. 2.5 M n-Butyl lithium in hexane (0.42 mL, 1.05 mmol) was addedfollowed by tri-isopropylborate (209 mg, 1.11 mmol). The mixture wasstirred at −78° C. for 30 minutes and then allowed to warm to roomtemperature. The solvent was removed in vacuo to provide theintermediate boronate. A mixture of this boronate,7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (282 mg, 0.60 mmol) andtetrakis(triphenylphosphine)palladium(0) (96 mg, 0.082 mmol) was heatedat reflux in 8.0 mL of ethylene glycol dimethyl ether and 5.0 mL ofsaturated sodium bicarbonate for 2 hours. The reaction was cooled toroom temperature, quenched with 4.1 mL of 1N sodium hydroxide, andpartitioned between ethyl acetate and brine. The layers were separatedand the ethyl acetate layer was dried over magnesium sulfate. Removal ofthe solvent in vacuo gave a residue which was purified by flash silicagel chromatography eluting with a gradient of ethyl acetate to 5%methanol in ethyl acetate to provide 163 mg (52% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrileas a yellow solid: mp 141-143° C.; ¹HNMR (DMSO-d₆/TFA): δ 3.19 (m, 2H),3.44 (m, 2H), 3.74 (m, 2H), 3.92 (s, 3H), 3.98 (m, 2H), 4.65 (s, 2H),7.63 (s, 1H), 7.89 (s, 1H), 8.38 (dd, J=9, 2 Hz, 1H), 8.46 (d, J=1Hz,1H), 8.76 (s, 1H), 8.98 (d, J=10 Hz, 1H), 9.00 (s, 1H), 9.33 (s, 1H),9.38 (d, J=2 Hz, 1H); MS (ES) m/z 520.1 (M+1). Analysis forC₂₇H₂₃Cl₂N₅O₂-0.5H₂O; Calcd: C, 61.27; H, 4.38; N, 13.46. Found: C,61.26; H, 4.57; N, 13.23.

EXAMPLE 504-(2,4-Dichloro-5-methoxyanilino)-6-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Morpholine (0.100 mL, 1.14 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-6-(5-formyl-3-thienyl)-3-quinolinecarbonitrile(Example 45) (150 mg, 0.33 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (340 mg, 1.60 mmol) was added followed by adrop of acetic acid. After stirring at 0° C. for 30 minutes the ice bathwas removed and the reaction mixture was stirred at room temperature for5.5 hours. The reaction was quenched by the addition of water and thenpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography eluting with a gradient of ethyl acetate to 10% methanolin ethyl acetate to provide 73 mg4-(2,4-dichloro-5-methoxyanilino)-6-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile(42% yield) as a bright yellow solid, mp softens at 130° C., melts at145-147° C.;

¹H NMR (DMSO-d₆) δ 2.50 (m, 4H), 3.59 (m, 4H), 3.73 (s, 2H), 3.87 (s,3H), 7.36 (s, 1H), 7.65 (s, 1H), 7.75 (s, 1H), 7.88 (d, J=8 Hz, 1H),8.01 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.49 (s, 1H), 8.77 (s, 1H); MS (ES)m/z 525.0 (M+1). Analysis for C₂₆H₂₂Cl₂N₄O₂S-0.25H₂O: Calcd: C, 58.92;H, 4.28; N, 10.57. Found: C, 58.78; H, 4.18; N, 10.31.

EXAMPLE 514-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-thienyl]-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile(Reference Example 13) (2.00 g, 4.25 mmol),tributyl[5-(1,3-dioxolan-2-yl)-2-thienyl]stannane (2.38 g, 5.35 mmol),and a catalytic amount of dichlorobis(triphenylphosphine)palladium(II)in 60 mL of dioxane was heated at reflux for 6 hours then stirred atroom temperature overnight. The mixture was concentrated in vacuo andpartitioned between ethyl acetate and saturated sodium chloride. Theorganic layer was dried over sodium sulfate and concentrated in vacuo. Aportion of this material was heated in ethyl acetate and the resultantsuspension was filtered to provide an analytical sample of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-thienyl]-3-quinolinecarbonitrileas a yellow solid, mp 174-177° C. dec.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.87 (s, 3H), 3.95-4.02 (m, 2H),4.05-4.13 (m, 4H), 6.13 (s, 1H), 7.38 (d, J=4 Hz, 1H), 7.59 (s, 1H),7.84 (d, J=4 Hz, 1H), 7.87 (s, 1H), 8.14 (d, J=2 Hz, 1H), 8.29 (dd, J=9,2 Hz, 1H), 8.75 (d, J=9 Hz, 1H), 9.16 (s, 1H); MS (ES) m/z 498.0, 500.0(M+1). Analysis for C₂₄H₁₇Cl₂N₃O₃S-0.75H₂O: Calcd: C, 56.31; H, 3.64; N,8.21. Found: C, 56.21; H, 3.84; N, 7.97.

EXAMPLE 524-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile

A solution of crude4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-thienyl]-3-quinolinecarbonitrile(Example 51) in 50 mL of tetrahydrofuran and 25 mL of 2N hydrochloricacid was stirred at room temperature overnight. Saturated sodiumbicarbonate was slowly added. Upon attempting to extract the productinto ethyl acetate a precipitate formed and was collected by filtrationwashing with water and ethyl acetate to provide 1.427 g of a brightyellow solid. A portion was heated in refluxing methanol and theresultant precipitate was filtered hot. The solid was washed withtetrahydrofuran, ethyl acetate and diethyl ether to provide ananalytical sample of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrileas a yellow solid, mp>300° C. (dec);

¹H NMR (DMSO-d₆) δ 3.85 (s, 3H), 7.19 (s, 1H), 7.64 (s, 1H), 7.98-8.07(m, 2H), 8.12 (d, J=4 Hz, 1H), 8.16 (d, J=2 Hz, 1H), 8.46 (s, 1H), 8.56(d, J=9 Hz, 1H), 9.96 (s, 1H); MS (ES) m/z 454.0, 456.0 (M+1). Analysisfor C₂₂H₁₃Cl₂N₃O₂S-0.25H₂O: Calcd: C, 57.59; H, 2.97; N, 9.16. Found: C,57.66; H, 2.91; N, 8.93.

EXAMPLE 534-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile

Morpholine (0.060 mL, 0.68 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (250 mg, 0.57 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (600 mg, 2.85 mmol) was added. Afterstirring at 0° C. for 1 hour, a catalytic amount of acetic acid wasadded and the reaction mixture was allowed to warm to room temperature.The reaction was quenched by the addition of water and then partitionedbetween saturated sodium bicarbonate and methylene chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography eluting with agradient of 10% methanol in methylene chloride to 20) methanol inmethylene chloride to provide 190 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrileas a light yellow solid (65% yield) mp 182-183° C.; MS (ES) m/z 509.0,511.0 (M+1). Analysis for C_(26H) ₂₂Cl₂N₄O₃-0.5H₂O: Calcd: C, 60.24; H,4.47; N, 10.81. Found: C, 60.40; H, 4.38; N, 10.52.

EXAMPLE 544-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-methoxyphenyl)ethenyl]-3-quinolinecarbonitrile

A mixture of7-iodo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 13) (250 mg, 0.53 mmol), 2-vinylanisole (0.11 mL,0.85 mmol), palladium(II)acetate (1.3 mg, 0.006 mmol) andtri-o-tolylphosphine (6.4 mg, 0.02 mmol) in 5 mL of triethylamine washeated at reflux for 12 hours. The mixture was concentrated in vacuo andthe resultant solid was partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulfate, filtered and concentratedto a small volume. The resultant solid was collected by filtration toprovide 150 mg (59% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[(E)-2-(4-methoxyphenyl)ethenyl]-3-quinolinecarbonitrileas a yellow solid, mp 216-220° C.;

¹H NMR (DMSO-d₆) δ 3.83 (s, 3H), 3.90 (s, 3H), 7.04 (d, J=9 Hz, 2H),7.44 (d, J=16 Hz, 1H), 7.63-7.73 (m, 4H), 7.90 (s, 1H), 7.99 (s, 1H),8.32 (d, J=9 Hz, 1H), 8.77 (d, J=9 Hz, 1H), 9.26 (s, 1H); MS (ES) m/z476.1, 478.1 (M+1). Analysis for C₂₆H₁₉Cl₂N₄O₂: Calcd: C, 65.56; H,4.02; N, 8.82. Found: C, 65.79; H, 3.98; N, 8.80.

EXAMPLE 554-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile

N-Methylpiperazine (0.100 mL, 0.90 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile(Example 52) (224 mg, 0.49 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide at room temperature. Sodiumtriacetoxyborohydride (500 mg, 2.36 mmol) was added followed by a dropof acetic acid. The reaction mixture was stirred at room temperatureovernight to give a yellow solution. The reaction was quenched by theaddition of water and then partitioned between saturated sodiumbicarbonate and ethyl acetate. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography eluting with 20% methanol inmethylene chloride to provide 108 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile(41%, yield) as a white solid, mp 206-208° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 2.87 (s, 3H), 3.05-3.72 (br m,8H), 3.88 (s, 3H), 4.47 (s, 2H), 7.39 (d, J=4 Hz, 1H), 7.57 (s, 1H),7.87 (s, 1H), 7.91 (d, J=4 Hz, 1H), 8.15 (d, J=2 Hz, 1H), 8.30 ((dd,J=9, 2 Hz, 1H), 8.79 (d, J=9 Hz, 1H), 9.20 (s, 1H); MS (ES) m/z 538.1,540.1 (M+1). Analysis for C₂₇H₂₅Cl₂N₅OS-0.5H₂O: Calcd: C, 59.23; H,4.79; N, 12.79. Found: C, 59.12; H, 4.43; N, 12.88.

EXAMPLE 567-[5-(4-Morpholinylmethyl)-2-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile

A mixture of 7-bromo-4-(4-phenoxyanilino)-3-quinolinecarbonitrile(Reference Example 10) (196.2 mg, 0.47 mmol),4-{[6-(tributylstannyl)-3-pyridinyl]methyl}morpholine (396.9 mg, 0.52mmol), and a catalytic amount ofdichlorobis(triphenylphosphine)palladium(II) in 3 mL of tetrahydrofuranwas heated at reflux for 4.5 days. The mixture was concentrated in vacuoand partitioned between ethyl acetate and saturated sodium chloride. Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The residue was purified by preparative thin layer chromatography, witha developing solvent of 10% methanol in ethyl acetate, to give 134.8 mgof7-[5-(4-morpholinylmethyl)-2-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrileas a yellow solid, mp 219-221° C.;

¹H NMR (DMSO-d₆) δ 9.42 (t, J=4 Hz, 4H), 3.59 (m, 6H), 7.03-7.15 (m,5H), 7.41 (m, 4H), 7.90 (dd, J=8, 2 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.39(dd, J=9, 2 Hz, 1H), 8.60 (d, J=3 Hz, 2H), 8.63 (s, 1H), 8.69 (d, J=2Hz, 1H), 9.95 (s, 1H); MS (ES) m/z 514.2 (M+1). Analysis forC₃₂H₂₇N₅O₂-0.5H₂O: Calcd: C, 73.54; H, 5.40; N, 13.40. Found: C, 73.54;H, 5.35; N, 13.08.

EXAMPLE 574-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile(Reference Example 13) (200.0 mg, 0.43 mmol),4-{[6-(tributylstannyl)-3-pyridinyl]methyl}morpholine (358.5 mg, 0.47mmol), and a catalytic amount ofdichlorobis(triphenylphosphine)palladium(I) in 4 mL of 1,4-dioxane washeated at reflux for 10 hours. The mixture was concentrated in vacuo andpartitioned between ethyl acetate and saturated sodium chloride. Theorganic layer was dried over sodium sulfate and concentrated in vacuo.The residue was purified by preparative thin layer chromatography, witha developing solvent of 10% methanol in ethyl acetate, to give 70.2 mgof4-(2,4-dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrileas a yellow solid, mp 220-22° C.;

¹H NMR (DMSO-d₆/TFA) δ 3.24-3.28 (m, 2H), 3.40-3.43 (m, 2H), 3.69 (t,J=12 Hz, 2H), 3.92 (s, 3H), 4.03 (d, J=13 Hz, 2H), 4.57 (s, 2H), 7.64(s, 1H), 7.91 (s, 1H), 8.22 (dd, J=8, 2 Hz, 1H), 8.43 (d, J=8 Hz, 1H),8.71 (dd, J=9, 2 Hz, 1H), 8.86 (d, J=2 Hz, 1H), 8.95 (s, 2H), 8.98 (s,1H), 9.36 (s, 1H); MS (ES) m/z 520.1 (M+1). Analysis forC₂₇H₂₃Cl₂N₅O₂-0.2H₂O: Calcd: C, 61.88; H, 4.50; N, 13.36. Found: C,61.87; H, 4.12; N, 13.25.

EXAMPLE 584-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(phenylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile

2-(Phenylsulfonyl)ethanamine (0.130 g, 0.68 mmol) was added to asuspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (250 mg, 0.57 mmol) in 3 mL of methylene chloride. Sodiumtriacetoxyborohydride (600 mg, 2.85 mmol) was added followed by 1 dropof acetic acid and the reaction mixture was stirred at room temperatureovernight. The reaction was quenched by the addition of saturated sodiumbicarbonate and then extracted with methylene chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash column chromatography eluting with 10%methanol in methylene chloride to provide 160 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(phenylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrileas a yellow solid (46% yield) mp 123-128° C.;

MS (ES) m/z 607.0, 609.0 (M+1). Analysis for C₃₀H₂₄Cl₂N₄O₄S-0.5H₂O:Calcd: C, 58.44; H, 4.08; N, 9.09. Found: C, 58.19; H, 3.87; N, 9.07.

EXAMPLE 594-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-(1H-pyrrol-1-yl)-3-quinolinecarbonitrile

An amount of 200 mg of7-amino-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile(0.51 mmol) was stirred in N,N-dimethylformamide (4.5 mL), and to thiswere added 50 mg (0.33 mmol) of 4-chloropyridine hydrochloride, and 100mg (0.77 mmol) of 2,5-dimethoxy-2,5-tetrahydrofuran. The reactionmixture was heated at 80° C. for 2 hours and subsequently cooled to roomtemperature, basified with saturated sodium bicarbonate solution, andextracted with ethyl acetate. The organic phase was dried over magnesiumsulfate, filtered through a pad of silica gel and evaporated. Theyellowish oily residue was purified by flash chromatography (ethylacetate/methanol/triethylamine, 40:4:1) to give 95 mg (42% yield) of anorange solid, mp 229-230° C.;

¹H NMR (DMSO-d₆) δ 9.90 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.84 (s,1H), 777 (s, 1H), 7.37 (broad s, 1H), 7.31 (t, J=2 Hz, 2H), 6.29 (t, J=2Hz, 2H), 4.02 (s, 3H), 3.88 (s, 3H); HRMS (EI) m/z 439.07161 (M+1).

EXAMPLE 604-(3-Bromoanilino)-6-(2-formyl-1H-pyrrol-1-yl)-3-quinolinecarbonitrile

An amount of 100 mg (0.29 mmol) of6-amino-4-[(3-bromophenyl)amino-3-quinolinecarbonitrile (preparedaccording to the procedure described in WO9843960-A1) was stirred in2-ethoxyethanol (2 mL) at room temperature. To this was added2-furaldehyde (42 mg, 0.43 mmol), and Amberlite IR-120 (29 mg), and themixture was stirred for 2 days at room temperature during which anorange precipitate was formed. The reaction mixture was filtered andevaporated to dryness to give a yellow solid (107 mg, 87% yield), mp94-95° C.;

¹H NMR (DMSO-d₆) δ 9.87 (s, 1H), 8.64 (d, J=2 Hz, 2H), 8.29 (d, J=2 Hz,1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=2 Hz, 1H), 7.50 (s, 1H),7.42-6.77 (m, 5H); MS (ES) m/z 417.0 (M+1). Analysis forC₂₁H₁₃BrN₄O.1.3H₂O: Calcd: C, 57.18; H, 3.54; N, 12.71. Found: C, 57.47;H, 3.46; N, 12.98.

EXAMPLE 614-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-(1H-1-pyrrol-1-yl)-3-quinolinecarbonitrile

A solution of6-amino-4-(3-chloro-4-fluoroanilino)-7-methoxy-3-quinolinecarbonitrile(prepared by the procedure described in WO9843960-A1) (0.20 g, 0.58mmol), 2,5-dimethoxytetrahydrofuran (0.1 mL, 0.77 mmol) and4-chloropyridine hydrochloride (50 mg, 0.33 mmol) inN,N-dimethylformamide (4.5 mL) was heated at 108° C. for 16 hours thencooled to room temperature. The reaction solution was partitionedbetween saturated sodium bicarbonate solution and ethyl acetate. Theorganic phase was passed through a pad of silica gel and dried to give alight brown solid. Addition of ether to the light brown solid followedby filtration gave 119 mg of a cream colored solid, mp 192.5-193.5° C.;

¹H NMR (DMSO-d₆) δ 9.80 (s, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 7.54 (m,2H), 7.47 (t, J=9 Hz, 1H), 7.33 (m, 1H), 7.20 (t, J=2 Hz, 2H), 6.28 (t,J=2.1 Hz, 2 H), 4.01 (s, 3H); HRMS (ES) m/z 393.0913 (M+1). Analysis forC₂₁H₁₄ClFN₄O-0.25H₂O: Calcd: C, 63.48; H, 3.68; N, 14.10; Cl, 8.92; F,4.78. Found: C, 63.83; H, 3.70; N, 13.85; Cl, 8.52; F, 4.86.

EXAMPLE 624-(3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile

By the procedure for Example 26, 500 mg (1.06 mmol) of7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrilewas reacted with 159 mg (1.06 mmol) of 4-formylphenylboronic acid and184 mg (0.16 mmol) of tetrakis(triphenylphosphine)palladium(0) in 7 mLof ethylene glycol dimethyl ether and 4 mL of saturated aqueous sodiumbicarbonate to provide 402 mg of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrileas a yellow solid after purification, mp>240° C. (dec);

¹H NMR (DMSO-d₆) δ 10.10 (s, 1H), 8.54-8.49 (m, 2H), 8.22 (s, 1H),8.14-8.04 (m, 4H), 7.99 (d, J=9 Hz, 1H), 7.53 (s, 1H), 7.37 (s, 1H),7.16 (s, 1H), 7.11 (d, J=8 Hz, 1H), 6.55 (d, J=9 Hz, 1H), 3.61 (s, 3H);MS (ES) m/z 496.0, 498.0 (M+1). Analysis for C₂₇H₁₈ClN₅OS.0.80CH₂Cl₂:Calcd: C, 59.21; H, 3.50; N, 12.42. Found: C, 59.59; H, 3.55; N, 12.50.

EXAMPLE 634-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

A mixture of 250 mg (0.50 mmol) of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrile45 mg (0.50 mmol) of morpholine, 36 mg (0.61 mmol) of acetic acid and 41mg (0.65 mmol) of sodium cyanoborohydride in 2 mL of ethanol, 0.5 mL ofdimethyl formamide and 2 mL of methylene chloride were allowed to reactat room temperature. After 12 hours, an additional 90 mg (1.03 mmol) ofmorpholine, 72 mg (1.2 mmol) of acetic acid and 82 mg (1.30 mmol) ofsodium cyanoborohydride were added to the mixture. After stirring for afurther 24 hours, the solvents were removed in vacuo, and the crudeproduct was washed with saturated aqueous sodium bicarbonate solution.Purification by silica gel chromatography (eluting with 95:5 ethylacetate/methanol, then 92:8 methylene chloride/methanol) provided 100 mgof4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrileas a yellow solid, mp 148-150° C.;

¹H NMR (DMSO-d₆) δ 9.95 (s, 1H), 8.67 (s, 1H), 8.47 (d, J=9 Hz, 1H),8.21 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.87 (d, J=8 Hz, 2H), 7.55 (s, 1H),7.49-7.46 (m, 3H; 7.21 (d, J=8 Hz, 1H), 7.17 (s, 1H), 6.46 (d, J=9 Hz,1H), 3.62 (s, 3H), 3.60 (t, J=5 Hz, 4H), 3.54 (s, 2H), 2.40 (t, J=4 Hz,4H); MS (ES) m/z 567.1, 569.2 (M+1). Analysis for C₃₁H₂₇ClN₆OS-0.5H₂O:Calcd: C, 64.63; H, 4.90; N, 14.59. Found: C, 64.28; H, 4.59; N, 14.66.

EXAMPLE 644-(2,4-Dichloro-5-methoxyanilino)-7-{1-[2-(4-morpholinyl)ethyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile

A mixture of 4-{2-[5-(tributylstannyl)-1H-imidazol-1-yl]ethyl}morpholine(Reference Example 68) (367 mg, 0.78 mmol),7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (260 mg, 0.61 mmol), anddichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.029 mmol) in 5 mLof dioxane was heated at reflux for 40 hours then concentrated in vacuo.The residue was partitioned between ethyl acetate and brine. The layerswere separated and the aqueous layer was extracted with ethyl acetate.The combined organic extracts were washed with water and brine, driedover magnesium sulfate and filtered. Removal of the solvent in vacuogave a residue which was purified by flash silica gel chromatographyeluting with 10% methanol in ethyl acetate to provide 80 mg (25% yield)of4-(2,4-dichloro-5-methoxyanilino)-7-{1-[2-(4-morpholinyl)ethyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrileas a yellow solid, mp 150° C. (decomposed);

¹HNMR (DMSO-d₆/TFA): δ 3.31 (m, 4H), 3.58 (t, J=4 Hz, 2H), 3.80 (m, 4H),3.92 (s, 3H), 4.83 (t, J=7 Hz, 2H), 7.56 (s, 1H), 7.89 (s, 1H), 8.14(dd, J=9, 1 Hz, 1H), 8.23 (d, J=1 Hz, 1H), 8.27 (d, J=1 Hz, 1H), 8.95(d, J=9 Hz, 1H), 9.31 (s, 1H), 9.50 (d, J=1 Hz, 1H); MS (ES) m/z 523.1(M+1). Analysis for C₂₆H₂₄Cl₂N₆O₂-0.5EtOAc: Calcd: C, 59.26; H, 4.97; N,14.81. Found: C, 59.56; H, 4.97; N, 14.63.

EXAMPLE 654-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(4-bromo-3-thienyl)methyl]-morpholine(Reference Example 69) in 88% yield as a white solid, mp 188-190° C.;

¹H NMR (DMSO-d₆) δ 2.40-2.45 (m, 4H), 3.47 (s, 2H), 3.55-3.65 (m, 4H),3.87 (s, 3H), 7.40 (s, 1H), 7.57 (d, J=3 Hz, 1H), 7.76 (s, 1H), 7.86 (d,J=3 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.56 (d, J=9 Hz, 1H),8.89 (s, 1H), 9.99 (s, 1H); MS (ES) m/z 525.0 (M+1). Analysis forC₂₆H₂₂Cl₂N₄O₂S: Calcd: C, 59.43; H, 4.22; N, 10.66. Found: C, 59.32; H,4.50; N, 10.55.

EXAMPLE 664-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl-3-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(3-bromo-2-thienyl)methyl]-morpholine(Reference Example 71) in 92% yield as a white solid, mp 98-100° C.;

¹NMR (DMSO-d₆) δ 2.45 (t, J=4 Hz, 4H), 3.60 (t, J=4 Hz, 4H), 3.78 (s,2H), 3.86 (s, 3H), 7.30-7.55 (m, 2H), 7.57 (s, 1H), 7.70-7.85 (m, 2H),8.03 (s, 1H), 8.55-8.65 (m, 2H), 10.01 (s, 1H); MS (ES) m/z 525.0 (M+1).Analysis for C₂₆H₂₂Cl₂N₄O₂S: Calcd: C, 59.43; H, 4.22; N, 10.66. Found:C, 59.22; H, 4.01; N, 10.75.

EXAMPLE 674-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(4-bromophenyl)]morpholine (preparedaccording to the procedure of U.S. Pat. No. 4,1397,04) in 68% yield as awhite solid, mp 235-237° C.:

¹H NMR (DMSO-d₆) δ 3.22 (t, J=5 Hz, 4H), 3.78 (t, J=5 Hz, 4H), 3.86 (s,3H), 7.10 (d, J=8 Hz, 2H), 7.35 (s, 1H), 7.71 (s, 1H), 7.79 (d, J=8 Hz,2H), 7.95-8.20 (m, 2H), 8.45-8.60 (m, 2H), 10.21 (s, 1H); MS (ES) m/z505.1 (M+1). Analysis for C₂₇H₂₂Cl₂N₄O₂-0.4H₂O: Calcd: C, 63.25; H,4.47; N, 10.93. Found: C, 63.33; H, 4.14; N, 10.74.

EXAMPLE 684-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 10,4-(2,4-dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and 4-[(5-bromo-3-thienyl)methyl]morpholine(Reference Example 73) in 96% yield as a white solid,

mp 118-190° C.; ¹H NMR (DMSO-d₆) δ 2.41 (t, J=7 Hz, 4H), 3.51 (s, 2H),3.60 (t, J=7 Hz. (4H), 3.86 (s, 3H), 7.41 (s, 1H), 7.49 (s, 1H),7.56-7.70 (m, 2H), 8.00-8.15 (m, 2H), 8.50-8.65 (m, 2H), 10.01 (s, 1H);MS (ES) m/z 525.0 (M+1). Analysis for C₂₆H₂₂Cl₂N₄O₂S-0.10CH₂Cl₂: Calcd:C, 58.81; H, 4.18; N, 10.49. Found: C, 59.54; H, 4.07; N, 10.15.

EXAMPLE 694-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 5,4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrilewas prepared from7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) and1-methyl-5-(tributylstannyl)-1H-pyrrole-2-carbaldehyde (preparedaccording to the procedure of Denat, F. J. Organometallic Chem. 423, 173(1992) in 64% yield as a light yellow solid, mp 200° C.(dec);

¹H NMR (DMSO-d₆) δ 3.87 (s, 3H), 4.00 (s, 3H), 6.66 (s, 1H), 7.19 (d,J=4 Hz, 1H), 7.42-8.09 (m, 4H), 8.60-8.70 (m, 2H), 9.65 (s, 1H), 10.10(s, 1H); MS (ES) m/z 451.1 (M+1). Analysis for C₂₃H₁₆Cl₂N₄O₂-0.3CH₂Cl₂:Calcd: C, 58.69; H, 3.50; N, 11.45. Found: C, 58.85; H, 3.27; N, 11.13.

EXAMPLE 704-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-(4-morpholinylmethyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile

4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile(Example 69) (150 mg, 0.33 mmol) and morpholine (35 mg, 0.4 mmol) weredissolved in 3 mL of methylene chloride and 2 mL ofN,N-dimethylformamide and cooled on an ice-water bath. Sodiumtriacetoxyborohydride (349 mg, 1.65 mmol) was added in portions. Theresultant suspension was warmed to room temperature, stirred overnight,and partitioned between water and ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, concentrated in vacuoand purified by flash silica gel column chromatography eluting with 3%methanol in methylene chloride to give 115 mg (66% yield) of product asa white solid, mp 208-2101° C.;

¹H NMR (DMSO-d₆) δ 2.35-2.45 (m, 4H), 3.50 (s, 2H), 3.55-3.65 (m, 4H),3.77 (s, 3H), 3.86 (s, 3H), 6.10 (s, 1H), 6.39 (s, 1H), 7.40 (s, 1H),7.70-7.85 (m, 2H), 7.90 (s, 2H), 8.52-8.65 (m, 9H), 9.97 (s, 1H); MS(ES) m/z 522.1 (M+1). Analysis for C₂₇H₂₅Cl₂N₅O₂-0.3CH₂Cl₂: Calcd: C,59.84; H, 4.70; N, 12.78. Found: C, 59.84; H, 4.66; N, 12.53.

EXAMPLE 714-(2,4-Dichloro-5-methoxyanilino)-7-{1-methyl-5-[(4-methyl-1-piperazinyl)methyl]-1H-pyrrol-2-yl}-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 70,4-(2,4-dichloro-5-methoxyanilino)-7-{1-methyl-5-[(4-methyl-1-piperazinyl)methyl]-1H-pyrrol-2-yl}-3-quinolinecarbonitrilewas prepared from4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile(Example 69) and N-methyl piperazine in 71% yield as a white solid, mp200° C. (dec);

¹H NMR (DMSO-d₆) δ 2.20 (s, 3H), 2.30-2.60 (m, 8H), 3.50 (s, 2H), 3.74(s, 3H), 3.86 (s, 3H), 6.08 (d, J=4 Hz, 1H), 6.37 (s, 1H), 7.35-7.90 (m,4H), 8.40-8.60 (m, 2H), 9.98 (s, 1H); MS (ES) m/z 535.1 (M+1). Analysisfor C₂₈H₂₈Cl₂N₆O-0.8CH₂Cl₂: Calcd: C, 57.32; H, 4.93; N, 13.93. Found:C, 57.23; H, 4.78; N, 14.11.

EXAMPLE 724-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(phenylsulfonyl)ethyl]amino}methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 70,4-(2,4-dichloro-5-methoxyanilino)-7-[1-methyl-5({[2-(phenylsulfonyl)ethyl]amino}methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrilewas prepared from4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile(Example 69) and 2-(phenylsulfonyl)ethylamine (Reference Example 49) in60% yield as a white solid, mp 178-1 80° C.;

¹H NMR (DMSO-d₆) δ 2.83 (t, J=7 Hz, 2H), 3.47 (t, J=7 Hz, 2H), 3.66 (s,3H), 3.69 (s, 2), 3.86 (s, 3H), 6.00 (d, J=4 Hz, 1H), 6.33 (s, 1H), 7.32(s, 1H), 7.58-7.82 (m, 7H), 7.90 (d, J=5 Hz, 2H), 8.45-8.60 (m, 2H),10.00 (s, 1H); MS m/z 620.0 (M+1). Analysis for C₃₁H₂₇Cl₂N₅O₃S-0.2H₂O:Calcd: C, 59.65; H, 4.41; N, 11.22. Found: C, 59.45; H, 4.18; N, 1.13.

EXAMPLE 734-(2,4-Dichloro-5-methoxyanilino)-7-1-methyl-5-({[2-(methylsulfonyl)ethyl]amino}methyl)-1H-pyrrol-2]-3-quinolinecarbonitrile

Using an analogous procedure to that described for Example 70,4-(2,4-dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(methylsulfonyl)ethyl]amino}-methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrilewas prepared from4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile(Example 69) and 2-(methylsulfonyl)ethylamine (Reference Example 72) in38% yield as a white solid, mp 160-164° C.;

¹H NMR (DMSO-d₆) δ 2.99 (t, J=7 Hz, 2H), 3.02 (s, 3H), 3.28 (t, J=7 Hz,2H), 3.73 (s, 3H), 3.78 (s, 2H), 3.86 (s, 3H), 6.12 (d, J=3 Hz, 1H),6.39 (s, 1H), 7.30-7.55 (m, 2H), 7.70-8.00 (m, 3H), 8.45-8.70 (m, 2H),9.97 (s, 1H); MS (ES) m/z 558.0 (M+1). Analysis forC₂₆H₂₅Cl₂N₅O₃S-0.15CH₂C₂: Calcd: C, 54.98; H, 4.45; N, 12.26. Found: C,54.99; H, 4.40; N, 11.90.

EXAMPLE 744-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile

2-(2-Aminoethyl)pyridine (0.065 mL, 0.54 mmol) was added to a suspensionof4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.45 mmol) in 5 mL of methylene chloride at roomtemperature. Sodium triacetoxyborohydride (480 mg, 2.25 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred atroom temperature overnight to give a yellow solution. The reaction wasquenched by the addition of water and then partitioned between saturatedsodium bicarbonate and ethyl acetate. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash silica gel column chromatography eluting with 10%methanol in methylene chloride to provide 55 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile(23% yield) as a yellow solid, mp 130-135° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.45-3.60 (m, 4H), 6.94 (d, J=4Hz, 1H), 7.52 (d, J=4 Hz, 1H), 7.62 (s, 1H), 7.89 (s, 1H), 7.99 (t, J=7Hz, 1H), 8.04 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.35 (d, J=9 Hz, 1H), 8.56(t, J=7 Hz, 1H), 8.87 (d, J=9 Hz, 1H), 8.94 (d, J=5 Hz, 1H), 9.30 (s,1H); HRMS (ES) m/z 544.12947 (M+1).

EXAMPLE 754-(2,4-Dichloro-5-methoxyanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile

N-Hydroxyethylpiperazine (0.072 mL, 0.55 mmol) was added to a suspensionof4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.45 mmol) in 3 mL of methylene chloride at roomtemperature. Sodium triacetoxyborohydride (480 mg, 2.25 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred atroom temperature overnight to give a yellow solution. The reaction wasquenched by the addition of water and then partitioned between saturatedsodium bicarbonate and ethyl acetate. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography eluting with 10% methanol inmethylene chloride to provide 50 mg of4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile(20% yield) as a light yellow solid, mp 176-181° C.; MS (ES) m/z 552.1,554.1 (M+1). Analysis for C₂₈H₂₇Cl₂N₅O₃-1.6H₂O: Calcd: C, 57.85: H,5.24; N, 12.05. Found: C, 58.07; H, 5.01; N, 11.67.

EXAMPLE 767-(5-{[bis(2-Hydroxyethyl)amino]methyl}-2-furyl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

Bis(2-hydroxyethyl)amine (0.052 mL, 0.55 mmol) was added to a suspensionof4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.45 mmol) in 5 mL of methylene chloride at roomtemperature. Sodium triacetoxyborohydride (480 mg, 2.25 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred atroom temperature for 2 days. The reaction was quenched by the additionof water and then partitioned between saturated sodium bicarbonate andethyl acetate. The organic layer was dried over sodium sulfate, filteredand concentrated in vacuo. The residue was purified by preparative thinlayer chromatography with a developing solvent of 5% methanol inmethylene chloride to provide 20 mg of7-(5-{[bis(2-hydroxyethyl)amino]methyl}-2-furyl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(8% yield) as a yellow solid, mp 155-160° C.; MS (ES) m/z 527.1, 529.1(M+1). Analysis for C₂₆H₂₄Cl₂N₄O₄-1.5H₂O: Calcd: C, 56.32: H, 4.91; N,10.10. Found: C, 56.43; H, 4.70; N, 9.78.

EXAMPLE 774-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile

The hydrochloride salt of 2-(methylsulfonyl)ethyl amine (ReferenceExample 72) (0.085 mg, 0.55 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.45 mmol) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (480 mg, 2.25 mmol) was added followed by a dropof acetic acid. The reaction mixture was allowed to warm to roomtemperature and stirred for 2 hours to give a yellow solution. Thereaction was quenched by the addition of water then partitioned betweensaturated sodium bicarbonate and ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography with adeveloping solvent of 5% methanol in methylene chloride to provide 50 mgof4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile(20% yield) as an off-white solid, mp 171-174° C.;

MS (ES) m/z 545.1, 547.1 (M+1). Analysis for C₂₅H₂₂Cl₂N₄O₄S: Calcd: C,55.05: H, 4.07; N, 10.27. Found: C, 54.87; H, 3.98; N, 9.94.

EXAMPLE 784-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile

Piperidine (0.047 mL, 0.44 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile(Example 6) (200 mg, 0.44 mmol) in 2 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (480 mg, 2.25 mmol) was added followed by a dropof acetic acid. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 hours to give a yellow solution. Thereaction was quenched by the addition of water then partitioned betweensaturated sodium bicarbonate and ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography with adeveloping solvent of 5% methanol in methylene chloride to provide 110mg of4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile(52% yield) as an off-white solid, mp 155-160° C.;

MS (ES) m/z 523.1, 525.1 (M+1). Analysis for C₂₇H₂₄Cl₂N₄OS: Calcd; C,61.95; H, 4.62; N, 10.70. Found: C, 61.65; H, 3.59; N, 10.48.

EXAMPLE 794-{2-chloro-4-fluoro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl}-3-thienyl]-3-quinolinecarbonitrile

By the procedure of Example 26, 310 mg (0.76 mmol) of7-bromo-4-(2-chloro-4-fluoro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 74) was reacted with 470 mg of crude4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}morpholineand 30 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 8mL of ethylene glycol dimethyl ether and 3.2 mL of saturated aqueoussodium bicarbonate to provide 262 mg of4-{2-chloro-4-fluoro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-quinolinecarbonitrileas a white solid after purification 185-187° C.;

¹H NMR (DMSO-d₆) δ 9.93 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.22 (s,1H), 8.16 (s, 1H), 8.06 (d, J=9 Hz, 1), 7.66 (m, 2H), 7.47 (d, J=9 Hz,1H), 3.86 (s, 3H), 3.75 (s, 2H), 3.60 (t, J=4 Hz, 4H), 2.47 (t, J=4 Hz,4H); MS (ES) m/z 509.0, 511.0 (M+1). Analysis for C₂₆H₂₂ClFN₄O₂S: Calcd:C, 61.35; H, 4.36; N, 11.01. Found: C, 60.96; H, 4.13; N, 10.69.

EXAMPLE 804-{2-Chloro-5-methoxy-4-methylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl}-3-quinolinecarbonitrile

By the procedure of Example 26, 100 mg (0.25 mmol) of7-bromo-4-(2-chloro-5-methoxy-4-methylanilino)-3-quinolinecarbonitrile(Reference Example 75) was reacted with 155 mg of crude4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}morpholineand 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) in 3mL of ethylene glycol dimethyl ether and 1.1 mL of saturated aqueoussodium bicarbonate to provide 108 mg of4-(2-chloro-5-methoxy-4-methylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrileas a white solid after purification, mp) 168-170° C.;

¹H NMR (DMSO-d₆) δ 9.9 (s, 1H), 8.56 (d, J=9 Hz, 1H), 8.52 (s, 1H), 8.19(s, 1H), 8.16 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.38 (s, 1H),7.14 (s, 1H, 3.80 (s, 3H), 3.75 (s, 2H), 3.60 (t, J=4 Hz, 4H), 2.47 (t,J=4 Hz, 4H), 2.21 (s, 3H); MS (ES) m/z 505.1, 507.1 (M+1). Analysis forC₂₇H₂₅ClN₄O₂S-0.3H₂O: Calcd: C, 63.53; H, 5.06; N, 10.98. Found: C,63.42; H, 4.81; N, 10.60.

EXAMPLE 814-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile

A mixture of 6-(4-morpholinylmethyl)-3-pyridinyltrifluoromethanesulfonate (65 mg, 0.20 mmol),7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (85mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.02mmol), anhydrous lithium chloride (25 mg, 0.60 mmol), andhexamethylditin (65 mg, 0.20 mmol) in 2 mL of 1,4-dioxane was heated atreflux for 16 hours. The mixture was cooled to room temperature, andpartitioned between ethyl acetate and 10% sodium carbonate solution. Thelayers were separated and the organic layer was washed with brine, anddried over magnesium sulfate. Removal of the solvent in vacuo gave aresidue which was purified by silica gel chromatography eluting with agradient of ethyl acetate to 10% methanol in ethyl acetate to provide 28mg (27% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrileas a yellow solid, mp 195-197° C.; ¹H NMR (DMSO-d₆/TFA) δ 3.39 (m, 4H),3.93 (m, 7H), 4.68 (s, 2H), 7.64 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.90 (s,1H), 8.42 (s, 1H), 8.43 (d, J=8 Hz, 1H), 8.49 (dd, J=8, 2 Hz, 1H), 8.96(d, J=9 Hz, 1H), 9.24 (d, J=2 Hz, 1H), 9.37 (s, 1H); MS (ES) m/z 520.0(M+1). Analysis for C₂₇H₂₃Cl₂N₅O₂: Calcd: C, 62.31; H, 4.45; N, 13.46.Found: C, 62.02; H, 4.14; N, 13.16.

EXAMPLE 827-[4,5-bis(4-Morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile

4-{[2-(4-Morpholinylmethyl)-3-thienyl]methyl}morpholine (ReferenceExample 24) (0.50 g, 1.77 mmol) was dissolved in 5 mL of anhydroustetrahydrofuran and the mixture was cooled to −78° C. n-Butyl lithium(2.5M in hexanes) (2.12 mL, 5.31 mmol) was added dropwise to thereaction mixture and stirring was continued for 30 minutes. The coolingbath was removed and the mixture stirred at room temperature for 20minutes. The reaction was then cooled to −78° C. and tributyltinchloride (1.5 mL, 5.31 mmol) was added. Stirring was continued for 15minutes at −78° C., and then at room temperature overnight. The reactionwas quenched with water and the product extracted into ethyl acetate.The organic layer was collected, dried over sodium sulfate and purifiedby flash column chromatography eluting with 5% methanol in methylenechloride to provide 859 mg of a yellow oil.

This oil was combined with3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyltrifluoromethanesulfonate (Reference Example 22) (652 mg, 1.25 mmol) anddichlorobis(triphenylphosphine)palladium(II) (150 mg, 0.15 mmol) in 10mL of dioxane and the mixture was heated at reflux for 6 hours. Thereaction was cooled to room temperature and concentrated in vacuo. Theresidue was purified by flash column chromatography eluting with agradient of 2% methanol in methylene chloride to 8% methanol inmethylene chloride, followed by 5% methanol in ethyl acetate as aneluent to provide 300 mg (36%) of7-[4,5-bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrileas a yellow solid, mp 120-124° C.;

¹H NMR (DMSO-d₆) δ 2.47 (br s, 8H), 3.49 (s, 2H), 3.50 (br m, 8H), 3.77(s, 2H), 3.87 (s, 3H), 4.04 (s, 3H), 7.39 (s, 1H), 7.68 (s, 1H), 7.77(s, 1H), 7.98 (s, 1H), 8.16 (s, 1H), 8.46 (s, 1H), 9.82 (s, 1H); MS (ES)m/z 654.0 (M+1). Analysis for C₃₂H₃₃Cl₂N₅O₄S-0.4H₂O+0.2C₄H₈O₂: Calcd: C,56.91; H, 5.20; N, 10.30. Found: C, 57.20; H, 5.10; N, 9.91.

EXAMPLE 834-(2,4-Dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile

7-Bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (3.00 g, 7.1 mmol) and 4-formylphenyl boronic acid(1.27 g, 8.5 mmol) were suspended in a mixture of ethylene glycoldimethyl ether (20 mL) and a saturated aqueous solution of sodiumbicarbonate (20 mL). Tetrakis(triphenylphosphine)palladium(0) (0.30 g,0.25 mmol) was added and the reaction mixture was heated to 80° C. Thereaction was stirred at 80° C. for 4 hours and then cooled to roomtemperature. The reaction was partitioned between ethyl acetate andsaturated sodium bicarbonate. The solid that precipitated was collectedby filtration, washed with ethyl acetate, methylene chloride and thenwater to yield 3.00 g (94%) of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrileas a yellow solid, mp 248-251° C.;

¹H NMR (DMSO-d₆) δ 3.87 (s, 3H), 7.43 (s, 1H), 7.78 (s, 1H), 7.99 (s,1H), 8.09 (s, 1H), 8.16 (m, 3H), 8.32 (s, 1H), 8.67 (t, J=9 Hz, 2H),10.10 (s, 1H), 10.11 (s, 1H); MS (ES) m/z 450.0 (M+1). Analysis forC₂₄H₁₅Cl₂N₃O₂-0.5CH₂Cl₂: Calcd: C, 56.91; H, 5.20; N, 10.30. Found: C,57.20; H, 5.10; N, 9.91.

EXAMPLE 84(2R)-1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-pyrrolidinecarboxamide

L-Prolineamide (71.5 mg, 0.6 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile(Example 83) (200 mg, 0.42 mmol) in 5 mL of methylene chloride and 1 mLof N,N-dimethylformamide at room temperature. The reaction was cooled to0° C. and sodium triacetoxyborohydride (500 mg, 2.36 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred at0° C. for 30 minutes and then at room temperature for 3 hours to give ayellow solution. The reaction was quenched by the addition of water andpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by flash column chromatographyeluting with 10% methanol in methylene chloride to provide 159 mg (69%)of(2R)1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-pyrrolidinecarboxamideas an off-white solid, mp 180-182° C.;

MS (ES) m/z 548.0 (M+1). Analysis for C₂₉H₂₅Cl₂N₅O₂-0.9H₂O: Calcd: C,61.84; H, 4.80; N, 12.42. Found: C, 61.86; H, 4.41; N, 12.29.

EXAMPLE 854-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(phenylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile

2-(Phenylsulfonlyl)ethanamine (Reference Example 49) (116.1 mg, 0.63mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile(Example 83) (200 mg, 0.42 mmol) in 5 mL of methylene chloride and 1 mLof N,N-dimethylformamide at room temperature. The reaction was cooled to0° C. and sodium triacetoxyborohydride (500 mg, 2.36 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred at0° C. for 30 minutes and then at room temperature for 3 hours to give ayellow solution. The reaction was quenched by the addition of water andthen partitioned between saturated sodium bicarbonate and ethyl acetate.The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography eluting with 10% methanol in methylene chloride toprovide 159 mg (61%) of4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[2-(phenylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrileas an off-white solid, mp 198-201° C.;

MS (ES) m/z 309.0 (M+2)⁺². Analysis for C₃₂H₂₆Cl₂N₄O₃S-0.8H₂O: Calcd: C,60.82; H, 4.41; N, 8.55. Found: C, 60.83; H, 4.27; N, 8.74.

EXAMPLE 86

4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile

Dimethylamine (2M solution in tetrahydrofuran) (0.31 mL, 0.63 mmol) wasadded to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile(Example 83) (200 mg, 0.42 mmol) in 5 mL of methylene chloride and 1 mLof N,N-dimethylformamide it room temperature. The reaction was cooled to0° C. and sodium triacetoxyborohydride (500 mg, 2.36 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred at0° C. for 30 minutes and then at room temperature for 2 hours to give ayellow solution. The reaction was quenched by the addition of water andpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by flash column chromatographyeluting with 15% methanol in methylene chloride to provide 123 mg (62%)of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrileas an off-white solid, mp 187-189° C.;

¹NMR (DMSO-d₆) δ 2.20 (s, 6H), 3.48 (s, 2H), 3.86 (s, 3H), 7.45 (m, 3H),7.70 (s, 1H), 7.85 (d, J=8 Hz, 2H), 8.0 (s, 1H), 8.11 (s, 1H), 8.54 (s,1H); 10.11 (br s, 1H); MS (ES) m/z 478.0 (M+1). Analysis forC₂₆H₂₂Cl₂N₄O-0.1H₂O: Calcd: C, 65.16; H, 4.68; N, 11.69. Found: C,64.95; H, 4.53; N, 11.61.

EXAMPLE 874-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(diethylamino)methyl]phenyl}-3-quinolinecarbonitrile

Diethylamine (0.065 mL, 0.9 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile(Example 83) (200 mg, 0.42 mmol) in 5 mL of methylene chloride and 1 mLof N,N-dimethylformamide at room temperature. The reaction was cooled to0° C. and sodium triacetoxyborohydride (500 mg, 2.36 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred it0° C. for 30 minutes and then at room temperature for 3 hours to give ayellow solution. The reaction was quenched by the addition of water andpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by flash column chromatographyelulting with 15% methanol in methylene chloride to provide 117 mg (55%)of4-(2,4-dichloro-5-methoxyanilino)-7-{4-[(diethylamino)methyl]phenyl}-3-quinolinecarbonitrileas an off-white solid, mp 191-195° C.;

¹H NMR (DMSO-d₆) δ 1.00 (t, J=7 Hz, 6H) 2.48 (m, 4H), 3.62 (s, 2H), 3.86(s, 3H), 7.50 (m, 3H), 7.71 (s, 1H), 7.85 (d, J=8 Hz, 2H), 7.99 (s, 1H),8.12 (s, 1H), 8.55 (s, 1H), 10.04 (br s, 1H); MS (ES) m/z 506.0 (M+1).Analysis for C₂₈H₂₆Cl₂N₄O-0.77H₂O: Calcd: C, 64.74; H, 5.34; N, 10.79.Found: C, 64.74; H, 4.97; No 10.74.

EXAMPLE 884-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(methylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile

2-(Methylsulfonyl)ethylamine hydrochloride salt (Reference Example 72)(77.2 mg, 0.63 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile(Example 83) (200 mg, 0.42 mmol) in 5 mL of methylene chloride and 1 mLof N,N-dimethylformamide at room temperature. The reaction was cooled to0° C. and sodium triacetoxyborohydride (500 mg, 2.36 mmol) was addedfollowed by a drop of acetic acid. The reaction mixture was stirred at0° C. for 30 minutes and then at room temperature overnight. Thereaction was quenched by the addition of water and partitioned betweensaturated sodium bicarbonate and ethyl acetate. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography eluting with 10%methanol in methylene chloride to provide 89 mg (38%) of4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[2-(methylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrileas an off-white solid, mp 245-246° C.;

MS (ES) m/z 556.0 (M+1). Analysis for C₂₇H₂₄Cl₂N₄O₃S-0.8H₂O: Calcd: C,56.89; H, 4.54; N, 9.82. Found: C, 56.87; H, 4.17; N, 9.75.

EXAMPLE 894-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile

4-Hydroxypiperidine (65 mg, 0.57 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile(Example 52) (200 mg, 0.44 mmol) in 4 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The mixture was cooled to 0° C. and sodiumtriacetoxyborohydride (470 mg, 2.20 mmol) was added followed by a dropof acetic acid. The reaction mixture was allowed to warm to roomtemperature and stirred at room temperature for 18 hours to give ayellow solution. The reaction was quenched by the addition of water andpartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by preparative thin layerchromatography with a developing solvent of 5% methanol in methylenechloride to provide 70 mg of4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile(30% yield) as an off-white solid, mp 120-123° C.; HRMS (ES): m/z539.10639 (m+1).

EXAMPLE 904-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-methoxyphenyl)ethynyl]-3-quinolinecarbonitrile

7-Bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (250 mg, 0.59 mmol), 1-ethynyl-4-methoxybenzene(0.23 mL, 1.77 mmol), copper iodide (20 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol) were heated atreflux in 0.5 mL of triethylamine and 4 mL of N,N-dimethylformamide for10 hours. The mixture was diluted with ethyl acetate and washed withbrine. The organic layer was dried over sodium sulfate and concentratedin vacuo. The residue was purified by preparative thin layerchromatography with a developing solvent of 1:1 ethyl acetate and hexaneto give 110 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[2-(4-methoxyphenyl)ethynyl]-3-quinolinecarbonitrile(39%) yield) as a yellow solid, mp 225-226° C.;

¹H NMR (DMSO-d₆) δ 3.85 (s, 3H), 3.91 (s, 3H), 7.07 (d, J=9 Hz, 2H),7.62 (s, 1H), 7.65 (d, J=9 Hz, 2H), 7.89 (s, 1H), 8.07 (dd, J=9, 2 Hz,1H), 8.10 (d, J=2 Hz, 1H), 8.83 (d, J=9 Hz, 1H), 9.33 (s, 1H); MS (ES)m/z 474.0, 476.0 (M+1). Analysis for C₂₆H₁₇Cl₂N₃O₂: Calcd; C, 65.84; H,3.61; N, 8.86. Found: C, 65.58; H, 3.66; N, 8.61.

EXAMPLE 914-(2,4-Dichloro-5-methoxyanilino)-7-[2-(2-pyridinyl)ethynyl]-3-quinolinecarbonitrile

7-Bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 8) (250 mg, 0.59 mmol), 2-ethynylpyridine (0.18 mL,1.77 mmol), copper iodide (20 mg, 0.11 mmol) andtetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol) were heated atreflux in 0.5 mL of triethylamine and 4 mL of N,N-dimethylformamide for5 hours. The mixture was diluted with ethyl acetate and washed withbrine. The organic layer was dried over sodium sulfate and concentratedin vacuo. The residue was purified by preparative thin layerchromatography with a developing solvent of 5% methanol in methylenechloride to give 110 mg of4-(2,4-dichloro-5-methoxyanilino)-7-[2-(2-pyridinyl)ethynyl]-3-quinolinecarbonitrile(42% yield) as a yellow solid, mp 238-240° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 3.94 (s, 3H), 7.60 (s, 1H),7.80-7.87 (m, 2H), 8.09 (d, J=8 Hz, 1H), 8.15 (dd, J=9, 2 Hz, 1H),8.30-8.35 (m, 2H), 8.90 (d, J=5 Hz, 1H), 8.96 (d, J=9 Hz, 1H), 9.39 (s,1H); MS (ES) m/z 445.1 (M+1). Analysis for C₂₄H₁₄Cl₂N₄O-1.5H₂O: Calcd;C, 61.02: H, 3.63; N, 11.86. Found: C, 60.97; H, 3.27; N, 11.98.

EXAMPLE 924-(2,4-Dichloro-5-methoxyanilino)-7-pyrrol-1-yl-3-quinolinecarbonitrile

An amount of 150 mg (0.42 mmol) of7-amino-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Reference Example 81) was stirred in N,N-dimethylformamide (3.5 mL),and to this were added 2,5-dimethoxytetrahydrofuran (83 mg, 0.63 mmol),and 4-chloropyridine hydrochloride (41 mg, 0.27 mmol). The reactionmixture was heated at 80° C. for 2 hours, and subsequently evaporated toa brown oil, basified with saturated sodium bicarbonate solution, andextracted with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate and evaporated. The yellow oily residue waspurified by preparative thin layer chromatography (40:4:1=ethylacetate:methanol:triethylamine), to give a yellow solid (84 mg, 49%yield; contains 17% 5-pyrrole-isomer), mp 205-207° C.;

¹H NMR (DMSO-d₆) δ 9.95 (s, 1H), 8.62 (d, J=9 Hz, 1H), 8.59 (s, 1H),8.10 (d, J=2 Hz, 1H), 8.04 (dd, J=9, 2 Hz, 1H), 7.77 (s, 1H), 7.71 (t,J=2 Hz, 2H), 7.43 (s, 1H), 6.37 (t, J=2 Hz, 2H), 3.87 (s, 3H); MS (ES)m/z 409.1 (M+1); HRMS (EI) 409.06058 (M+1). Analysis forC₂₁H₁₄Cl₂N₄O.2H₂O: Calcd: C, 56.59; H, 4.04; N, 12.58. Found: C, 56.39;H, 4.01; N, 12.30.

EXAMPLE 934-(2,4-Dichloro-5-methoxyanilino)-7-{(2-[(dimethlylamino)methyl]-1H-pyrrol-1-yl}-3-quinolinecarbonitrile

An amount of 400 mg (0.98 mmol) of4-(2,4-dichloro-5-methoxyanilino)-7-pyrrol-1-yl-3-quinolinecarbonitrile(Example 92) was stirred in ethanol (8 mL), tetrahydrofuran (1.6 mL),and ethyl acetate (2.4 mL), and to this were added paraformaldehyde (43mg, 1.47 mmol), and dimethylamine hydrochloride (208 mg, 2.6 mmol). Thereaction mixture was stirred at reflux for 16 hours, and subsequentlyevaporated, basified with saturated sodium bicarbonate solution, andextracted with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate and evaporated. The gummy residue was purifiedby flash chromatography (40:4:1=ethyl acetate:methanol:triethylamine),to give a cream solid (306 mg, 49% yield), mp 157-158° C.;

¹H NMR (DMSO-d₆/trifluoroacetic acid) δ 9.61 (bs, 1H), 8.69 (s, 1H),8.68 (m, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.30-7.29 (m,2H), 6.68-6.67 (m, 1H), 6.43 (m, 1H), 4.43 (s, 1H), 4.41 (s, 1H), 3.87(s, 3H), 2.57 (s, 3H), 2.55 (s, 3H); MS (ES) m/z 466.1 (M+1); HRMS (EI)466.11952 (M+1). Analysis for C₂₄H₂₁Cl₂N₅O: Calcd: C, 61.81; H, 4.54; N,15.02. Found: C, 61.72; H, 4.64; N, 14.90.

EXAMPLE 947-[5-(1,3-Dioxolan-2-yl)-3-thienyl]-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile

A mixture of7-bromo-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile(Reference Example 82) (1.00 g, 2.25 mmol),tributyl[5-(1,3-dioxolan-2-yl)-3-thienyl]stannane (1.19 g, 2.67 mmol),and a catalytic amount of dichlorobis(triphenylphosphine)palladium(II)in 30 mL of dioxane was heated at reflux for 6 hours and then stirred atroom temperature overnight. The solution was concentrated and trituratedwith diethyl ether to provide 980 mg of a yellow solid. An analyticalsample was obtained by flash column chromatography eluting with ethylacetate to provide7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrileas a yellow solid, imp 194-196° C.;

MS (ES) m/z 521.1 (M+1). Analysis for C₃₀H₂₄N₄O₃S-0.75H₂O: Calcd: C,67.46; H, 4.81; N, 10.49. Found: C, 67.48; H, 4.52; N, 10.35.

EXAMPLE 954-[3-Methyl-4-(2-pyridinylmethoxy)anilino]7-[5-(4-morpholinylmethyl)-3-thienyl-3-quinolinecarbonitrile

A solution of 980 mg of crude7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile(Example 94) in 40 ml of tetrahydrofuran and 20 mL of 2N hydrochloricacid was stirred at room temperature for 6 hours. Saturated sodiumbicarbonate was slowly added. Ethyl acetate was added resulting in alarge amount of insoluble material. The entire mixture was filtered andthe solid was washed with water and ethyl acetate to provide 549 mg ofthe intermediate aldehyde. The organic layer of the filtrate was driedover magnesium sulfate, filtered and concentrated in vacuo to provide anadditional 303 mg of the intermediate aldehyde.

Morpholine (0. 180 mL, 0. 21 mmol) was added to a suspension of thealdehyde (250 mg, 0.53 mmol) in 4 mL of methylene chloride and 1 mL ofN,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (540 mg, 2.55 mmol) was added followed by adrop of acetic acid. After stirring at 0° C. for 20 minutes the ice bathwas removed and the reaction mixture was stirred it room temperature for5 hours. The reaction was quenched by the addition of saturated sodiumbicarbonate and then partitioned between saturated sodium bicarbonateand ethyl acetate. The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was triturated withmethanol to provide 93 mg of4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile(33% yield) as an off-white solid, mp 217-219° C.;

MS (ES) m/z 548.1 (M+1). Analysis for C₃₂H₂₉N₅O₂S: Calcd: C, 70.18; H,5.34; N, 12.79. Found: C, 69.94; H, 5.17; N, 12.52.

EXAMPLE 964-(2,4-Dichloro-5-methoxyanilino)-7-(2-formyl-1-methyl-1H-imidazol-5-yl)-3-quinolinecarbonitrile

N-methylpiperazine (2.40 g, 20 mmol) was dissolved in 60 mL of hexanesand 50 mL of tetrahydrofuran. The mixture was cooled to 0° C. andn-butyl lithium (2.5M in hexanes) (8 mL, 20 mmol) was added slowly tothe reaction mixture and stirring was continued for 40 minutes. To thereaction mixture was added 1-methyl-1H-imidazole-2-carbaldehyde(prepared by the procedure described in Alcalde, E., Tetrahedron, 52,15171 (1996) in portions, followed by further stirring for 15 minutes.To this was added N,N,N′,N′-tetramethylethylenediamine (4.64 g, 40mmol), followed by n-butyl lithium (2.5M in hexanes) (16 mL, 40 mmol),while maintaining the reaction mixture at 0° C. The reaction was stirredfor 18 hours, then 50 mL of tetrahydrofuran was added. The reaction wasthen cooled to −46° C. and tributyltin chloride (13.2 g, 40 mmol)dissolved in tetrahydrofuran (20 mL) was added. Stilling was continuedfor 15 minutes at −46° C., then the cooling bath was removed. Thereaction was stirred for 6 hours, then quenched with saturated sodiumbicarbonate and the product extracted into diethyl ether. The organiclayer was collected, dried over sodium sulfate and purified by flashcolumn chromatography eluting with 30% ethyl acetate in hexanes toprovide 3.9 g of1-methyl-5-tributylstannanyl-1H-imidazole-2-carbaldehyde as a yellowoil.

1-Methyl-5-tributylstannanyl-1H-imidazole-2-carbaldehyde (1.2 g, 30mmol), 7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(0.5 g, 1.2 mmol) (Reference Example 8),dichlorobis(triphenylphosphine)palladium(II) (100 mg, 0.10 mmol) andtriethylamine (0.133 g, 1.3 mmol) in 10 mL of dioxane was heated atreflux for 4 hours. The reaction was cooled to room temperature andpartitioned between ethyl acetate and a saturated solution of sodiumbicarbonate. The organic layer was collected, dried over sodium sulfateand passed through a plug of magnesol. After concentrating the solution,the resulting residue was purified by flash column chromatography,eluting with 5% methanol in methylene chloride to provide a semi-solid.This was triturated with a 1:1 mixture of diethyl ether/hexane toprovide 370 mg (68%) of4-(2,4-dichloro-5-methoxyanilino)-7-(2-formyl-1-methyl-1H-imidazol-5-yl)-3-quinolinecarbonitrileas a yellow solid, mp 186-189° C.; ¹H NMR (DMSO-d₆) δ 3.87 (s, 3H), 4.07(s, 3H), 7.44 (s, 1H), 7.72 (s, 1H), 7.79 (s, 1H), 7.93 (d, 1H), 8.17(s, 1H), 8.65 (s, 1H), 8.67 (d, 1H), 9.81 (s, 1H), 10.14 (s, 1H); MS(ES) m/z 452.0 (M+1). Analysis for C₂₂H₁₅Cl₂N₅O₂-0.7H₂O: Calcd: C,56.70; H, 3.56; N, 13.93. Found: C, 56.79; H, 3.77; N, 14.11.

EXAMPLE 974-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(1-piperazinylmethyl)phenyl]-3-quinolinecarbonitrile

A mixture of tert-butyl4-{4-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-3-cyano-7-quinolinyl]benzyl}-1-piperazinecarboxylate(Example 137) (2.05 g, 30.8 mmol) and 60 mL of methanolic HCl wasstirred for 20 hours. The precipitated solid was collected byfiltration, washed with ether, suspended in saturated aqueous sodiumbicarbonate and stirred for 1 hour. The solids were collected byfiltration, washing with water and diethyl ether to provide 1.97 g (99%)of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(1-piperazinylmethyl)phenyl]-3-quinolinecarbonitrileas a yellow solid: mp 140-142° C.; MS 566 (M+H)+.

EXAMPLE 984-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-isopropyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile

A mixture of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(1-piperazinylmethyl)phenyl]-3-quinolinecarbonitrile(Example 97) (0.25 g, 0.44 mmol) and sodium cyanoborohydride (0.08 g,1.27 mmol) in 30 mL of acetone was stirred for 1 hour. Two drops ofglacial acetic acid were added and the mixture was stirred for 20 hours.The precipitated solid was collected by filtration, washed with diethylether, suspended in aqueous saturated sodium bicarbonate and stirred for1 hour. The solids were collected by filtration, washing with water anddiethyl ether. The solid was purified by flash silica gel chromatographyeluting with a gradient of 5% methanol in dichloromethane to 20%methanol in dichloromethane to provide 0.075 g (28%) of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}-amino)-7-{4-[(4-isopropyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrileas a yellow solid: mp 193-195° C.; MS 608 (M+H)+.

EXAMPLE 99(E)-3-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-propenoicAcid

(E)-tert-Butyl3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-propenoate(Example 142) (75 mg, 0.16 mmol) in 2 mL of dichloromethane and 0.3 mLof trifluoroacetic acid was stirred at room temperature for 5 hours. Themixture was diluted with diethyl ether and hexane. The resultant solidwas collected by filtration to provide 45 mg (47% yield) of(E)-3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-propenoicacid as a yellow solid: mp 237-240° C.; MS 398.0, 400.1 (M+H)+.

EXAMPLE 100(1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)aceticAcid

Ethyl(1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)acetate(Example 144) (160 mg, 0.27 mmol) and 3 mL of 1 N sodium hydroxide in 3mL of methanol was stirred at room temperature for 2.5 hours. Themethanol was removed in vacuo and the aqueous solution was acidifiedwith HCl. The solid was collected by filtration to provide 150 mg (97%yield) of(1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)aceticacid as a yellow solid: mp 239-240° C.; MS 424.2, 426.2 (M+H)+.

EXAMPLE 1014-(2,4-Dichloro-5-methoxyanilino)-7-[4-(hydroxymethyl)phenyl]-3-quinolinecarbonitrile

To a mixture of4-(2,4-dichloro-5-methoxyanilino)-7-[4-(formylphenyl]-3-quinolinecarbonitrile(Example 83) (400 mg, 0.90 mmol) in 15 mL of methanol at 0° C., wasadded sodium borohydride (54 mg, 1.42 mmol) in portions. The mixture wasallowed to warm to room temperature and stirred at room temperature for2 hours. The mixture was partitioned between water and ethyl acetate.The organic layer was concentrated and purified by flash columnchromatography, eluting with 1:1 hexane:ethyl acetate, to give 220 mg(54% yield) of4-(2,4-dichloro-5-methoxyanilino)-7-[4-(hydroxymethyl)phenyl]-3-quinolinecarbonitrileas a yellow solid: mp 264-267° C.; MS 449.9, 451.9 (M+H)+.

EXAMPLE 1027-[4-(Chloromethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

To a mixture of4-(2,4-dichloro-5-methoxyanilino)-7-[4-(hydroxymethyl)phenyl]-3-quinolinecarbonitrile(Example 101) (210 mg, 0.5 mmol) in 20 mL of dichloromethane and 75 μLof pyridine at −30° C. was added 1-chloro-N,N, 2-trimethyl propenylamine(81 mg, 0.65 mmol). The mixture was stirred at −30° C. for 2 hours andthen at room temperature overnight. The mixture was concentrated and theresidue was purified by flash column chromatography, eluting with 1:1hexane:ethyl acetate, to give 90 mg (38% yield) of7-[4-(chloromethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrileas a yellow solid: mp 236-239° C.;

MS 468.0, 470.0 (M+H)+.

EXAMPLE 1034-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-quinolinecarbonitrile

A mixture of7-[4-(chloromethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile(Example 102) (0.25 g, 0.53 mmol), 1H-1,2,3-triazole (0.31 mL, 5.3mmol), sodium hydroxide (85 mg, 2.1 mmol), and sodium iodide (40 mg,0.26 mmol) was heated at 80° C. for 4 hours. The mixture was partitionedbetween ethyl acetate and water and the organic layer was dried oversodium sulfate and concentrated. The residue was purified by flashcolumn chromatography, eluting with 1% methanol in dichloromethane togive 90 mg (34% yield) of4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-quinolinecarbonitrileas a yellow solid: mp 239-240° C.; MS 501.0, 503.0 (M+H)+.

EXAMPLE 1044-(2,4-Dichloro-5-methoxyanilino)-7-(1H-pyrrol-2-yl)-3-quinolinecarbonitrile

A solution of tert-butyl2-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-1H-pyrrole-1-carboxylate(90 mg, 0.177 mmol) (Example 164) in 2.0 mL of trifluoroacetic acid wasstirred at 0° C. for 1 hour, then allowed to warm to room temperatureand stirred for 2 hours. The resulting mixture was adjusted to pH of 8-9with saturated aqueous sodium bicarbonate and then diluted with water.The crude product was collected by filtration, washed with water andpurified by flash column chromatography to give 65 mg (90%) of4-(2,4-dichloro-5-methoxyanilino)-7-(1H-pyrrol-2-yl)-3-quinolinecarbonitrileas a yellow solid: mp 240° C. dec; MS 409.2 (M+H)+.

EXAMPLE 1054-[(2,4-Dichloro-5-methoxyanilino]-7-[4-(1H-tetraazol-5-yl)phenyl]-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyphenylamino)-7-tributylstannanyl-3-quinolinecarbonitrile(200 mg, 0.32 mmol) (Reference Example 83),5-(4-bromophenyl)-1H-tetrazole (106 mg, 0.47 mmol) anddichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.016 mmol) in 3 mLof N,N-dimethylformamide was heated at reflux for 7 hours. The reactionmixture was diluted with dichloromethane, concentrated on silica gel,and purified by flash column chmomatography to give 39 mg (25%) of4-[(2,4-dichloro-5-methoxyphenylamino]-7-[4-(1H-tetraazol-5-yl)phenyl]-3-quinolinecarbonitrileas a white solid: mp 270° C. dec; MS 487.6 (M+H)+.

EXAMPLE 1064-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile

A mixture of 2-[[(6-bromo-3-pyridinyl)methyl](methyl)amino]ethanol (245mg, 10 mmol),7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanlyl]anilino}-3-quinolinecarbonitrile(471 mg, 1.0 mmol) (Reference Example 14),tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol), andhexamethylditin (328 mg, 1.0 mmol) in 10 mL of 1,4-dioxane was heated atreflux for 16 hours. The mixture was concentrated and the residue waschromatographed over silica gel, eluting with a gradient of methylenechloride to methylene chloride/methanol (3:1) to provide4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrileas a yellow solid, 198 mg (36%): mp 197-199° C.;

MS 556.4 (M+H)+.

EXAMPLE 107 Methyl1-{[6-(4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino]-3-cyano-7-quinolinyl)-3-pyridinyl]methyl}-4-piperidinecarboxylate

A mixture of 6-bromonicotinaldehyde (186 mg, 1.0 mmol),7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(471 mg, 1.0 mmol) (Reference Example 14),tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol), andhexamethylditin (328 mg, 1.0 mmol) in 10 mL of 1,4-dioxane was heated atreflux for 9 hours and concentrated. The residue was suspended in 10 mLof methylene chloride and 2 mL of N,N-dimethylformamide. Methylisonipecotate (286 mg, 2.0 mmol) was added followed by two drops ofglacial acetic acid and the mixture was stirred for 30 minutes. Sodiumcyanoborohydride (1.0 g, 15.9 mmol) was added, and the mixture wasstirred for 1 hour. Water was added to quench the reaction. The productwas extracted into methylene chloride, and the combined extracts werewashed with brine, dried, and concentrated. The residue waschromatographed over silica gel, eluting with a gradient of 10% to 20%methanol in ethyl acetate to provide methyl1-{[6-(4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3-pyridinyl]methyl}-4-piperidinecarboxylateas a yellow solid, 164 mg (26%): mp 135-137° C.; MS 624.2 (M+H)+.

EXAMPLE 1084-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile

To a solution of 1-(6-bromo-3-pyridinyl)-4-ethylpiperazine (405 mg, 1.5mmol) in 10 mL of tetrahydrofuran at −78° C. was added n-butyllithlium(2.5M in hexanes, 0.60 mL, 1.5 mmol). The solution was stirred at −78°C. for 15 minutes. Tributyltin chloride (585 mg, 1.8 mmol) was added,and the mixture was warmed to room temperature. The reaction wasquenched with water, and the product was extracted with ethyl acetate.The organic layer was separated, dried over magnesium sulfate, andconcentrated. The crude product was used directly in the next step. Amixture of this crude organotin compound,7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(236 mg, 0.50 mmol) (Reference Example 14),tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.027 mmol), anddichlorobis(triphenylphosphine)palladium(II) (30 mg, 0.043 mmol) in 5 mLof 1,4-dioxane and 0.5 mL of dimethylformamide was heated at reflux for10 h and concentrated. The residue was chromatographed over silica gel,eluting with a gradient of ethyl acetate to 30% methanol in ethylacetate to provide4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}-amino)-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrileas a yellow solid, 149 mg (51%): mp 246-248° C.; MS 580.9 (M+H)+.

EXAMPLE 1094-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile

A mixture of 4-[(5-bromo-2-pyridinyl)methyl]morpholine (141 mg, 0.55mmol), hexamethylditin (180 mg, 0.55 mmol),tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.055 mmol) in 5 mL of1,4-dioxane was heated at reflux for 45 minutes.7-Bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(200 mg, 0.42 mmol) (Reference Example 14) was added, followed bytetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) and 0.5 mLof dimethylformamide. The resulting reaction mixture was heated atreflux for 6 hours. After cooling to room temperature, the mixture wasconcentrated in vacuo and the residue was treated with water. Theaqueous suspension was extracted with methylene chloride. The organicphase was washed with brine and dried over sodium sulfate. Removal ofthe solvent gave a semisolid residue. The residue was purified bypreparative thin layer chromatography developing with 10% methanol indichloromethane to provide 63 mg (26%) of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}-amino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrileas a yellow solid: mp 233-235° C.; MS 568.05 (M+H)+.

EXAMPLE 1104-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-thiomorpholinyl)-3-pyridinyl]-3-quinolinecarbonitrile

A mixture of 4-[(5-bromo-2-pyridinyl)thiomorpholine (119.2 mg, 0.46mmol), hexamethylditin (150 mg, 0.46 mmol),tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) in 4.0 mLof 1,4-dioxane was heated at reflux for 3.5 hours.7-Bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(200 mg, 0.42 mmol) (Reference Example 14) was added followed bytetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol) and 0.5 mLof dimethylformamide. The resulting reaction mixture was heated atreflux for 19 hours. According to the work up procedure and purificationreported for Example 109, 109 mg (45%) of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-thiomorpholinyl)-3-pyridinyl]-3-quinolinecarbonitrilewas obtained as a yellow solid: mp>260° C.; MS 569.8 (M+H)+.

EXAMPLE 1114-(2,4-Dichloro-5-methoxyanilino)-7-[3-(morpholin-4-ylmethyl)-pyridin-2-yl]-3-quinolinecarbonitrile

A mixture of7-bomo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (494mg, 1.17 mmol) (Reference Example 8), hexamethylditin (383 mg, 1.17mmol) and tetrakis(triphenylphosphine)palladium(0) (68.2 mg, 0.059) in1.5 mL of DMF(anhydrous) was head at 100° C. for 1.5 hours.4-[2-Bromo-3-pyridinyl)methyl]morpholin (15 mg, 0.59 mmol) was addedfollowed by tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.059 mmol)and 6 mL of 1,4-dioxane. The resulting reaction mixture was heated atreflux for 22 h. According to the work up procedure and purificationreported for Example 109, 28 mg (9%) of4-(2,4-dichloro-5-methoxyanillino)-7-[3-(morpholin-4-ylmethyl)-pyridin-2-yl]-3-quinolinecarbonitrilewas obtained as a yellow solid: mp 151-154° C.; MS 520.1 (M+H)+.

EXAMPLE 1124-(2,4-Dichloro-5-methoxyanilino)-7-(3-formyl)-3-quinolinecarbonitrile

A mixture of4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile (0.118g, 0.25 mmol) (Reference Example 13), 3-formylphenylboronic acid(0.075g, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g,0.012 mmol), 10 mL of ethylene glycol dimethyl ether and 8 mL of asaturated sodium bicarbonate solution was placed in the vessel formicrowave under nitrogen. The microwave heating (PROLABO unit, mono-moderegimen) was continued for 1 hour at 80° C. with stirring. The reactionmixture was cooled to room temperature and then partitioned betweenwater and ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography eluting with chloroform to provide 0.096 g (86%) of4-(2,4-dichloro-5-methoxyanilino)-7-(3-formyl)-3-quinolinecarbonitrile250-252° C.; MS 448.0 (M+H)+.

EXAMPLE 1134-(2,4-Dichloro-5-methoxyanilino)-7-{3-[4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile

N-Methylpiperazine (0.045 mL, 0.37 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(3-formyl)-3-quinolinecarbonitrile(0.130 g 0.30 mmol) (Example 112) in 3 mL of methylene chloride and 1 mLof N,N-dimethylformamide. The reaction mixture was cooled to 0° C. andsodium triacetoxyborohydride (0.330 g, 1.57 mmol) was added. Afterstirring at 0° C. for 1.5 hour, a catalytic amount of acetic acid wasadded and the reaction mixture was kept for 2 hours at 0° C. and thenfor 2 hours at room temperature. The reaction was quenched by theaddition of water and then partitioned between saturated sodiumbicarbonate and methylene chloride. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography eluting with 10% methanol in methylenechloride to provide 0.070 g (45%) of4-(2,4-dichloro-5-methoxyanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrilemp 104-106° C.; MS 532.1 (M+H)+.

EXAMPLE 1144-(2,4-Dichloro-5-methoxyanilino)-7-(2-formylphenyl)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.250g, 0.59 mmol) (Reference Example 8), 2-formylphenylboronic acid (0.149g, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.060mmol), 15 mL of ethylene glycol dimethyl ester and 10 mL of a saturatedsodium bicarbonate solution was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 80° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.200 g (75%) of4-(2,4-dichloro-5-methoxyanilino)-7-(2-formyl)-3-quinolinecarbonitrile:mp 252-253° C., MS 448.0 (M+H)+.

EXAMPLE 1154-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

Morpholine (0.140 mL, 1.6 mmol) was added to a suspension of4-(2,4-dichloro-5-methoxyanilino)-7-(2-formyl)-3-quinolinecarbonitrile(0.310 g, 0.69 mmol) (Example 114) in 5 mL of methylene chloride and 1mL of N,N-dimethylformamide. The reaction mixture was cooled to 0° C.and sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added. Afterstirring at 0° C. for 1.5 hour, a catalytic amount of acetic acid wasadded and the reaction mixture was kept for 2 hours at 0° C. and thenfor 2 hours at room temperature. The reaction was quenched by theaddition of water and then partitioned between saturated sodiumbicarbonate and methylene chloride. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography eluting with 10% methanol in methylenechloride to provide 0.154 g (43%) of4-(2,4-dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)phenyl]3-quinolinecarbonitrile:mp 107-109° C., MS 519.1 (M+H)+.

EXAMPLE 1164-(2,4-Dichloro-5-methoxyanilino)-7-(1-naphthyl)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 1-naphthylboronic acid (0.120 g,0.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol), 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.116 g (75%) of4-(2,4-dichloro-5-methoxyanilino)-7-(1-naphthyl)-3-quinolinecarbonitrile:mp 192-193° C., MS 470.0 (M+H)+.

EXAMPLE 1174-(2,4-Dichloro-5-methoxyanilino)-7-(2-naphthyl)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 2-naphthylboronic acid (0.120 g,0.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol) 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.135 g (87%) of4-(2,4-dichloro-5-methoxyanilino)-7-(2-naphthyl)-3-quinolinecarbonitrile:mp 243-244° C., MS 470.0 (M+H)+.

EXAMPLE 118N-{3-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]phenyl}acetamide

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 3-acetamidophenylboronic acid(0.120 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g,0.012 mmol), 15 mL of dimethylformamide and 10 mL of a saturatedsolution of sodium bicarbonate was placed in the vessel for microwaveunder nitrogen. The microwave heating (PROLABO unit, mono-mode regimen)was continued for 1 hour at 130° C. with stirring. The reaction mixturewas cooled to room temperature and then partitioned between water andethyl acetate. The organic layer was dried over sodium sulfate, filteredand evaporated. The residue was purified by column chromatographyeluting with chloroform to provide 0.105 g (65%) ofN-{3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]phenyl}acetamide:mp 262-2630° C., MS 476.9 (M+H)+.

EXAMPLE 1197-(1-Benzofuran-2-yl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 1-benzofuranboronic acid (0.100 g,0.62 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol), 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.130 g (86%) of7-(1-benzofuran-2-yl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile:mp 276-277° C., MS 460.0 (M+H)+.

EXAMPLE 1207-(-Benzothien-2-yl)-4-2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 1-benzothiopheneboronic acid (0.120g, 0.67 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol), 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.107 g (67%) of7-(1-benzothien-2-yl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile:mp 269-270° C., MS 475.8 (M+H)+.

EXAMPLE 1214-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzoic Acid

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 4-carboxyphenylboronic acid (0.100g, 0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol), 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.085 g (86%) of4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzoic acid:mp 282-283° C., MS 65.8 (M+H)+.

EXAMPLE 1224-(2,4-Dichloro-5-methoxyanilino)-7-(3-nitrophenyl)-3-quinolinecarbonitrile

A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (0.141g, 0.33 mmol) (Reference Example 8), 3-nitrophenylboronic acid (0.090 g,0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.012mmol), 15 mL of dimethylformamide and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 130° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.115 g (75%) of4-(2,4-dichloro-5-methoxyanilino)-7-(3-quinolinecarbonitrile: mp287-288° C., MS 464.9 (M+H)+.

EXAMPLE 1234-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile

To a mixture of 4-(4-bromobenzyl)morpholine (0.20 g, 0.78 mmol)(Reference Example 46), potassium acetate (0.23 g, 0.23 mmol),bis(pinacolato)diboron (0.218 g, 0.86 mmol) in 5 mL dimethylsulfoxidewas added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (0.032 g, 0.039 mmol). The mixture wasstirred at 80° C. for 2 hours, cooled, diluted with ethyl acetate,washed with water, dried over MgSO₄ and evaporated under high vacuum toprovide ˜0.2 g of a dark solid material.

A mixture of this material,4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanlyl]anilino}-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (0.06 g, 0.01 mmol) (Reference Example 120),15 mL of dimethylformamide and 10 mL of a saturated solution of sodiumbicarbonate was placed in the vessel for microwave under nitrogen. Themicrowave heating (PROLABO unit, mono-mode regimen) was continued for 1hour at 130° C. with stirring. The reaction mixture was cooled to roomtemperature and then partitioned between water and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and evaporated.The residue was purified by column chromatography eluting withchloroform to provide 0.046 g (73%) of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile:mp 260-262° C., MS 597.0 (M+H)+.

EXAMPLE 1247-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-3-quinolinecarbonitrile

To a mixture of 4-[4-bromo-2-(4-morpholinylmethyl)benzyl]morpholine(0.354 g, 0.1 mmol) (Reference Example 37), potassium acetate (0.23 g,0.23 mmol), bis(pinacolato)diboron (0.218 g, 0.86 mmol) in 5 mL ofdimethylsulfoxide was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.032 g, 0.039 mmol). The mixture was stirred at 80° C.for 2 hours, cooled, diluted with ethyl acetate, washed with water,dried over magnesium sulfate and evaporated under high vacuum to provide˜0.4 g of a dark solid material.

A mixture of this material,4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (0.09 g, 0.015 mmol) (Reference Example 120),15 mL of dimethylformamide and 10 mL of a saturated solution of sodiumbicarbonate was placed in the vessel for microwave under nitrogen. Themicrowave heating (PROLABO unit, mono-mode regimen) was continued for 1hour at 130° C. with stirring. The reaction mixture was cooled to roomtemperature and then partitioned between water and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and evaporated.The residue was purified by column chromatography eluting withchloroform to provide 0.09 g (82%) of7-[3,4-bis(4-morpholinylmethyl)phenyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-3-quinolinecarbonitrile:mp 228-2300° C., MS 348.4 (M+2H)+2.

EXAMPLE 1254-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile

To a mixture of 4-[(4-bromo-2-thienyl)methyl]morpholine (0.26 g) 0.1mmol) (prepared according to the procedure of U.S. Pat. No. 5,866,572),potassium acetate (0.23 g. 0.23 mmol) and bis(pinacolato)diboron (0.218g) 0.86 mmol) in 5 mL of dimethylsulfoxide was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.032 g, 0.039 mmol). The mixture was stilled at 80° C.for 2 hours, cooled, diluted with ethyl acetate, washed with water,dried over magnesium sulfate and evaporated under high vacuum to provide0.4 g of a dark solid material.

A mixture of this material,4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (0.09 g 0.015 mmol) (Reference Example 120),15 mL of dimethylformamide and 10 mL of a saturated solution of sodiumbicarbonate was placed in the vessel for microwave under nitrogen. Themicrowave heating (PROLABO unit, mono-mode regimen) was continued for 1hour at 130° C. with stirring. The reaction mixture was cooled to roomtemperature and then partitioned between water and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and evaporated.The residue was purified by column chromatography eluting withchloroform to provide 0.035 g (0.37%) of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile:mp 238-240° C., MS 602.8 (M+H)+.

EXAMPLE 1264-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile

To the mixture of 1-[(4-bromo-2-thienyl)methyl]-4-methylpiperazine(0.275 g, 0.1 mmol) (Reference Example 97), potassium acetate (0.23 g,0.23 mmol), bis(pinacolato)diboron (0.218 g, 0.86 mmol) in 5 mL ofdimethylsulfoxide was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (0.032 g, 0.039 mmol). The mixture was stirred at 80° C.for 2 hours, cooled, diluted with ethyl acetate, washed with water,dried over MgSO₄ and evaporated under high vacuum to provide ˜0.4 g of adark solid material.

A mixture of this material,4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (0.285 g, 0.05 mmol) (Reference Example 120),15 mL of dimethylformamide and 10 mL of a saturated solution of sodiumbicarbonate was placed in the vessel for microwave under nitrogen. Themicrowave heating (PROLABO unit, mono-mode regimen) was continued for 1hour at 130° C. with stirring. The reaction mixture was cooled to roomtemperature and then partitioned between water and ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered and evaporated.The residue was purified by column chromatography eluting withchloroform to provide 0.118 g (38%) of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile:mp 162-164° C., MS 615.7 (M+H)+.

EXAMPLE 1274-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-(4-methoxyphenyl)3-quinolinecarbonitrile

A mixture of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-6-methoxy-7-quinolinyltrifluoromethanesulfonate (0.285 g, 0.05 mmol) (Reference Example 120),4-methoxyphenylboronic acid (0.151 g, 1.0 mmol),tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.060 mmol), 15 mL ofethylene glycol dimethyl ether and 10 mL of a saturated solution ofsodium bicarbonate was placed in the vessel for microwave undernitrogen. The microwave heating (PROLABO unit, mono-mode regimen) wascontinued for 1 hour at 80° C. with stirring. The reaction mixture wascooled to room temperature and then partitioned between water and ethylacetate. The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by column chromatography elutingwith chloroform to provide 0.190 g (72%) of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-(4-methoxyphenyl)-3-quinolinecarbonitrile:mp 227-229° C., MS 527.8 (M+H)+.

EXAMPLE 1284-{2,4-Dichloro-5-methoxyphenyl)amino}-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile

A mixture of4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzoic acid(0.464 g, 0.10 mmol) (Example 121) and 3.0 mL of thionyl chloride wasrefluxed for 3 hours. The excess thionyl chloride was removed to provide0.5 g of the intermediate chloroanhydride.

The chloroanhydride was dissolved in 10 mL of tetrahydrofuran andstirred with 2.0 mL of morpholine at room temperature for 2 hours.Solvent and excess morpholine were removed in vacuum. The residue waspurified by column chromatography eluting with chloroform/methanol 30:1to provide 0.288 g (54%) of4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile:mp 162-164° C., MS 533.1 (M+H)+.

EXAMPLE 1294-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(4-morpholinylcarbonyl)phenyl]-3-quinolinecarbonitrile

A mixture of 7-bromo4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}-amino)-3-quinolinecarbonitrile(0.118 g, 0.25 mmol) (Reference Example 14), 4-carboxybenzeneboronicacid (0.083 g, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0)(0.020 g, 0.012 mmol), 10 mL of ethylene glycol dimethyl ether and 8 mLof asaturated solution of sodium bicarbonate was placed in the vesselfor microwave under nitrogen. The microwave heating (PROLABO unit,mono-mode regimen) was continued for 1 hour at 80° C. with stirring. Thereaction mixture was cooled to room temperature and then partitionedbetween water and ethyl acetate. The organic layer was dried over sodiumsulfate, filtered and evaporated to provide 0.070 g of crude acid.

A mixture of crude acid and 3.0 mL of thionyl chloride was heated atreflux for 3 hours. The excess thionyl chloride was removed to provide0.07 g of crude chloroanhydride. The chloroanhydride was dissolved in 10mL of tetrahydrofuran and stirred with 2.0 mL of morpholine at roomtemperature for 2 hours. Solvent and excess morpholine were removed invacuum. The residue was purified by column chromatography, eluting withchloroform-methanol 30:1 to provide 0.045 g (31%) of4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(4-morpholinylcarbonyl)phenyl]-3-quinolinecarbonitrile:mp 98-101° C., MS 581.2 (M+H)+.

The Examples in Table 4 are listed with the chemical name, melting pointand/or mass spectral data and the Example procedure used in thepreparation of the compound.

TABLE 4 Ex- Ex. am- Chemical Pro. ple Name MP ° C. MS Used 1304-(2,4-dichloro-5- 205-207 494.3,  1 methoxyanilino)-7-{4-[(2- 496.3methoxy)ethoxy]phenyl }- (M + H) + 3-quinolinecarbonitrile 1314-(2-chloro-5-methoxy- 110-115 491.0  1 anilino)-7-[5-(4-morpho- (M +H) + linylmethyl)-3-thienyl]-3- quinolinecarbonitrile 1324-[4-(benzyloxy)-3- foam 660.2  35 chloroanilino]-7-[3,4- (M + H) +bis(4-morpholinyl- methyl)phenyl]-3- quinolinecarbonitrile 1337-[3,4-bis(4-morpholinyl- 186-188 597.9  35 methyl)phenyl]-4-(2- (M +H) + chloro-5-methoxy-4- methylanilino)-3- quinolinecarbonitrile 1344-{3-chloro-4-[(1-methyl- 230-232 581.2  1 1H-imidazol-2- (M + H) +yl)sulfanyl]anilino}-7-{4- [(4-hydroxy-1-piperi- dinyl)methyl]phenyl}-3- quinolinecarbonitrile 135 4-{3-chloro-4-[(1-methyl- 202-203 290.5 70 1H-imidazol-2-yl)sul- (M + 2H)2 + fanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)- methyl]phenyl}-3- quinolinecarbonitrile 1364-{3-chloro-4-[(1-methyl- 158-160 283.3  70 1H-imidazol-2-yl)sul- (M +2H)2 + fanyl]anilino}-7-[4-(1- pipendinylmethyl)phenyl]-3-quinolinecarbonitrile 137 tert-butyl-4-{4-[4-({3- 184-186 666.4  1chloro-4-[(1-methyl-1H- (M + H) + imidazol-2-yl)sulfanyl]-phenyl}amino)-3-cyano-7- quinolinyl]benzyl}-1- piperazinecarboxylate 1384-({3-chloro-4-[(1- 205-210 553.4  10 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{4-[(4-morpholinyl-methyl)-phenyl}-3-quino- linecarbonitrile 139 4-(2,4-dichloro-5- 230-232446.0  2 methoxyanilino)-7-[(E)-2- (M + H) + phenylethenyl]-3-quinolinecarbonitrile 140 4-(2,4-dichloro-5- 210-212 444.0,  91methoxyanilino)-7-(2- 446.0 phenylethynyl)-3- (M + H) +quinolinecarbonitrile 141 4-(2,4-dichloro-5- 223-225 458.0  91methoxyanilino)-7-[2-(4- (M + H) + methylphenyl)ethynyl]-3-quinolinecarbonitrile 142 tert-butyl (E)-3-[3-cyano- 203-204 470.0  24-(2,4-dichloro-5- (M + H) + methoxyanilino)-7- quinolinyl]-2-propenoate143 4-(2,4-dichloro-5-  245 398.0  91 methoxyanilino)-7-(3- (dec) 400.1hydroxy-1-propynyl)-3- (M + H) + quinolinecarbonitrile 144ethyl(1-{4-[3-cyano-4- 142-144 603.3  41 (2,4-dichloro-5- 605.4methoxyanilino)-7- (M + H) + quinolinyl]benzyl)}-4- piperidinyl)acetate145 ethyl 1{4-[3-cyano-4- 78-80 588.9,  41 (2,4-dichloro-5- 590.9methoxyanilino)-7- (M + H) + quinolinyl]benzyl}-2- piperidinecarboxylate146 4-(2,4-dichloro-5- 190-191 466.93  91 methoxyanilino)-7-[3-(4- 468.8morpholinyl)-1-pro- (M + H) + pynyl]-3-quinoline- carbonitrile 1471-{4-[3-cyano-4-(2,4-  230 560.83 100 dichloro-5-inethoxy- (dec) 562.8anilino)-7-quinolinyl]- (M + H) + benzyl}-2-piperidinecar- boxylic acid148 ethyl 1-(4-{3-cyano-4- 67-70 588.8,  41 [(2,4-dichloro-5- 590.8methoxyphenyl)amino]-7- (M + H) + quinolinyl}benzyl)-3-piperidinecarboxylate 149 1-(4-{3-cyano-4-[(2,4-  235 560.8, 100dichloro-5-methoxy- (dec) 562.8 phenyl)amino]-7- (M + H) +quinolinyl}benzyl)-3- piperidinecarboxylic acid 150 4-[(2,4-dichloro-5-248-251 567.2,  41 methoxyphenyl)amino]-7- 569.2 {4-[(1,1-dioxido-4-(M + H) + thiomorpholinyl)methyl] phenyl}-3-quinoline- carbonitrile 1514-[(2,4-dichloro-5- 244-247 549.2,  41 methoxyphenyl)amino]-7- 551.2{4-[(1-oxido-4-thiomor- (M − H) − pholinyl)methyl]phenyl}-3-quinolinecarbonitrile 152 7-(3-chloro-1-propynyl)- 215-217 416.26, 1024-[(2,4-dichloro-5- 418.26 methoxyphenyl)amino]-3- (M + H) +quinolinecarbonitrile 153 4-[(2,4-dichloro-5- 216-219 535.3,  41methoxyphenyl)amino)-7- 537.3 [4-(4-thiomorpho- (M + H) +linylmethyl)phenyl]-3- quinolinecarbonitrile 1544-{3-chloro-4-[(1-methyl- 224-226 557.1  41 1H-imidazol-2-yl)sul- (M +H) + fanyl]anilino}-7-[5-(4- morpholinylmethyl)-2- furyl]-3-quinoline-carbonitrile 155 4-{3-chloro-4-[(1-methyl- 214-215 553.2  411H-imidazol-2-yl)sul- (M − H) − fanyl)anilino}-7-[5-(1-piperidinylmethyl)-2- furyl]-3- quinolinecarbonitrile 1564-{3-chloro-4-[(1-methyl- 212-215 583.1  41 1H-imidazol-2-yl)sul- (M +H) + fanyl)anilino}-7-{5-[(4- ethyl-1-piperazinyl)- methyl]-2-furyl}-3-quinolinecarbonitrile 157 4-{3-chloro-4-[(1-methyl- 206-209 600.1  411H-imidazol-2-yl)sul- (M + H) + fanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1- piperazinyl]methyl}-2- furyl)-3-quinoline-carbonitrile 158 4-({3-chloro-4-[(1- 258-261 486.2  1methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-(5-formyl-2-furyl)-3- quinolinecarbonitrile 1594-{3-chloro-4-[(1-methyl- 147-149 586.9  41 1H-imidazol-2-yl)sul- (M +H) + fanyl]anilino}-7-{5-[(4- hydroxy-1-piperidinyl)-methyl]-2-thienyl}-3- quinolinecarbonitrile 1604-{3-chloro-4-[(1-methyl-  100 570.8  41 1H-imidazol-2-yl)sul- (dec)(M + H) + fanyl]anilino}-7-[5-(1- piperidinylmethyl)-2-thienyl)-3-quinoline- carbonitrile 161 4-{3-chloro-4 [(1-methyl- 145-147616.4  41 1H-imidazol-2-yl)sul- (M + H) + fanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1- piperazinyl]methyl}-2- thienyl)-3-quinoline-carbonitrile 162 4-(2,4-dichloro-5-  175 453.0  70 methoxyanilino)-7-[5- (dec) (M + H) + (hydroxymethyl)-1- methyl-1H-pyrrol-2-yl]-3-quinolinecarbonitrile 163 4-(2,4-dichloro-5- 231-232 454.0  1methoxyanilino)-7-(3- (M + H) + formyl-2-thienyl)-3-quinolinecarbonitrile 164 tert-butyl 2-[3-cyano-4-  135 509.0  1(2,4-dichloro-5- (dec) (M + H) + methoxyanilino)-7-quinolinyl]-1H-pyrrole-1- carboxylate 165 7-[1,1′-biphenyl]-4-yl-4-235-236 496.1  1 (2,4-dichloro-5- (M + H) + methoxyanilino)-3-quinolinecarbonitrile 166 4-(2,4-dichloro-5- 105-108 497.2  11methoxyanilino)-6- (M + H) + methoxy-7-[3-(4- morpholinyl)-1-propynyl]-3-quinoline-carbonitrile 167 4-(4-chloro-5-methoxy-2- dec > 505  33methylanilino)-7-[5-(4-  108 (M + H) + morpholinylmethyl)-3-thienyl]-3-quinoline- carbonitrile 168 7-[4.5-bis(4-morpho- 158-160 618 1 linylmethyl)-2-thienyl]-4- (M + H) + (4-phenoxyanilino)-3-quinolinecarbonitrile 169 7-[4,5-bis(4-morpho- 173-175 672  1liny)methyl)-2-thienyl]-4- (M + H) + {3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sul- fanyl]anilino}-3- quinolinecarbonitrile 1704-{3-chloro-4-[(1-methyl-  130 494.9 106 1H-imidazol-2-yl)sul- (dec) (M− H) − fanyl]anilino}-7-(5- formyl-2-pyridinyl)-3- quinolinecarbonitrile171 4-{3-chloro-4-[(1-methyl- 125-130 595.4 107 1H-imidazol-2-yl)sul-(M + H) + fanyl)anilino}-7-{5-](4- ethyl-1-piperazinyl)-methyl]-2-pyridinyl}-3- quinolinecarbonitrile 1724-{3-chloro-4-[(1-methyl- 194-196 291.8 106 1H-imidazol-2-yl)sul- (M +2H) + 2 fanyl]anilino}-7-{5-[(4- hydroxy-1-piperizinyl)-methyl]-2-pyridinyl}-3- quinolinecarbonitrile 1734-{3-chloro-[(1-methyl- 183-185 635.5 106 1H-imidazol-2-yl)sul- (M +H) + fanyl]anilino}-7-(5-{[4- (1-pyrrolidinyl)-1- piperidinyl]methyl}-2-pyridinyl)-3-quinoline- carbonitrile 174 7-(3-aminophenyl)-4-(2,4-221-222 434.9 117 dichloro-5-methoxy- (M + H) + anilino)-3-quinoline-carbonitrile 175 1-{[6-(4-{3-chloro-4-[(1- 166-168 610.2 100methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3- pyrdinyl]methyl}-4- piperidinecarboxylic acid 1761-{6-[3-cyano-4-(2,4- 186-188 576.2, 107 dichloro-5-methoxy- (M + H) +phenylamino)-quinolin-7- yl)-pyridin-3-ylmethyl}-piperidine-4-carboxylic acid methyl ester 177 1-{6-[3-cyano-4-(2,4-  150562.3 100 dichloro-5-methoxy- (dec) (M + H) phenylamino)-quinolin-7-yl]-pyridin-3- ylmethyl}-piperidine-4- carboxylic acid 1784-({3-chloro-4-[(1- 205-207 500.7 108 methyl-1H-imidazol-2- (M − H) −yl)sulfanyl]phenyl}amino)- 7-(5-chloro-2-pyri-dinyl)-3-quinoline-carbonitrile 179 4-[(2,4-dichloro-5- 232-234 532.9 108methoxyphenyl)amino]-7- (M + H) + [5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3- quinolinecarbonitrile 180 4-({3-chloro-4-[(1- 175-177566.4 106 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-[5-(1-pyridinyl]-3- quinolinecarbonitrile 181 4-({3-chloro-4-[(1-  150581.2 108 methyl-1H-imidazol-2- (dec) (M + H) +yl)sulfanyl]phenyl}amino)- 6-[5-(4-ethyl-1- piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile 182 4-({3-chloro-4-[(1- 238-241 568.1 108methyl]-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-6-[5-(4-morpho- linylmethyl)-2-pyridinyl]- 3-quinolinecarbonitrile 1834-({3-chloro-4-[(1- 260-262 579.3 108 methyl-1H-imidazol-2- (M − H)yl)sulfanyl]phenyl}amino)- 6-{5-[(4-methyl-1- piperazinyl)methyl]-2-pyridinyl}-3-quinoline- carbonitrile 184 4-({3-chloro-4-[(1- 276-278554.1 108 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-6-[6-(4-morpholinyl)-3- pyridinyl]-3-quinoline- carbonitrile 1854-(2,4-dichloro-5- >260 506.0 108 methoxyanilino)-7-[6-(4- (M + H) +morpholinyl)-3- pyridinyl]-3-quinoline- carbonitrile 1864-(2,4-dichloro-5- >260 508.8 108 methoxyanilino)-7-[2-(4- (M + H) +morphpolinyl)-5- pyrimidinyl)-3-quinoline- carbonitrile 1874-{3-chloro-4-[(1-methyl- 225-227 567.7 108 1H-imidazol-2- (M + H) +yl)sulfanyl]anilino}-7-[5- (4-morpholinylmethyl)-2-pyridinyl]-3-quinoline- carbonitrile 188 4-(2,4-dichloro-5- 212-215533.1 108 methoxyanilino)-7-{5-[(4- (M + H) + methyl-1-piperazinyl)-methyl]-2-pyridinyl}-3- quinolinecarbonitrile 1894-{3-chloro-4-[(1-methyl- 197-199 581.1 108 1H-imidazol-2-yl)sul- (M +H) + anyl]anilino}-7-{5-[(4- methyl-1-pipeiazinyl)---methyl]-2-pyridinyl}-3- quinolinecarbonitrile 1904-{3-chloro-4-[(1-methyl- >250 553.8 108 1H-imidazol-2-yl)su- (M + H) +fanyl]anilino}-7-[6-(4- morpholinyl)-3-pyri- dinyl]-3-quinoline-carbonitrile 191 4-{3-chloro-4-[(1-methyl- >250 555 1081H-imidazol-2-yl)su- (M + H) + fanyl]anilino}-7-[2-(4-morpholinyl)-5-pyri- midinyl]-3-quinoline- carbonitrile 1924-(2,4-dichloro-5- 187-189 539.1,  41 methoxyanilino)-7-{5-[(4- 541.2hydroxy-1-piperi- (M + H) + dnyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 193 4-(2,4-dichloro-5- 176-178 612 106methoxyanilino)-7-{6-[4- (M + H) + (4-morpholinyl- methyl)phenoxy)-3-pyridinyl)-3-quinoline- carbonitrile 194 4-(2,4-dichloro-5- 210-212449.7,  83 methoxyanilino)-7-(4- 451.7 methoxyphenyl)-3- (M + H) +quinolinecarbonitrile 195 4-{3-chloro-4-[(1-methyl- 254-256 580.8 1081H-imidazol-2- (M + H) + yl)sulfanyl]anilino}-7-[6-(4-ethyl-1-piperazinyl)-3- pyridinyl]-3- quinolinecarbonitrile 1964-{3-chloro-4-[(1-methyl- 227-279 566.8 108 1H-imidazol-2-yl)sul- (M +H) + fanyl]anilino}-7-[6-(4- methyl-1-piperazinyl)-3-pyridinyl-3-quinoline- carbonitrile 197 4-(2,4-dichloro-5- 264-266 533.0108 methoxyanilino)-7-[6-(4- (M + H) + ethyl-1-piperazinyl)-3-pyridinyl]-3-quinoline- carbonitrile 198 4-(2,4-dichloro-5- 240-242 519108 methoxyanilino)-7-[6-(4- (M + H) + methyl-1-piperazinyl)-3-pyridinyl]-3-quinoline- carbonitrile 199 4-{3-chloro-4-[(1-methyl-232-234 567.8 108 1H-imidazol-2- (M + H) + yl)sulfanyl]anilino}-7-[6-(4-morpholinylmethyl)-2- pyridinyl]-3-quinoline- carbonitrile 2004-(2,4-dichloro-5- 181-183 520.2 108 methoxyanilino)-7-[6-(4- (M + H) +morpholinylmethyl)-2- pyridinyl]-3-quinoline- carbonitrile 2014-{3-chloro-4-[(1-methyl- 214-216 595.2 108 1H-imidazol-2-yl)sul- (M +H) + fanyl]anilino}-7-{6-[(4- ethyl-1-piperazinyl)-methyl]-2-pyridinyl}-3- quinolinecarbonitrile 2024-{3-chloro-4-[(1-methyl- 157-159 581.4 108 1H-imidazol-2-yl)sul- (M +H) + fanyl)anilino}-7-{6-[(4- methyl-1-piperazinyl)-methyl)-2-pyridinyl}-3- quinolinecarbonitrile 203 4-({3-chloro-4-[(1-205-207 568.4 108 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-[4-(4-morpholinyl- methyl)-2-pyridinyl]-3-quinolinecarbonitrile 204 4-[(2,4-dichloro-5- 180-182 520.2 108methoxyphenyl)amino]-7- (M + H) + [4-(4-morpholinyl-methyl)-2-pyridinyl]-3- quinolinecarbonitrile 205 4-({3-chloro-4-[(1-150-153 595.2 108 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{4-[(4-ethyl-1-pipera- zinyl)methyl]-2-pyridinyl}-3-quinoline- carbonitrile 206 4-({3-chloro-4-[(1- 208-210581.2 108 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl)phenyl}amino)-7-{4-[(4-methyl-1- piperazinyl)methyl]-2- pyridinyl}-3-quinoline-carbonitrile 207 4-({3-chloro-4-[(1-  195 567.8 166methyl-1H-imidazol-2- (dec) (M + H) + yl)sulfanyl]phenyl}amino)-7-[3-(4-morpholinyl- methyl)-2-pyridinyl]-3- quinolinecarbonitrile 2084-({3-chloro-4-[(1- 187-190 595.38 106 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{3-[(4-ethyl-1- piperazinyl)methyl-2-pyridinyl}-3-quinoline- carbonitrile 209 4-({3-chloro-4-[(1- 217-220581.35 106 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-{3-[(4-methyl-1- piperazinyl)methyl]-2- pyridinyl}-3-quinoline-carbonitrile 210 4-({3-chloro-4-[(1-  230 621.2 110methyl-1H-imidazol-2- (dec) (M + H) + yl)sulfanyl]phenyl}amino)-7-{6-[4-(1-pyrrolidinyl)- 1-piperidinyl-3- pyridinyl}-3-quinoline-carbonitrile 211 4-({3-chloro-4-[(1- >260 551.0 110methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinyl)-3- pyridinyl]-3-quinoline- carbonitrile 2124-({3-chloro-4-[(1- 224-226 555.9 110 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{6-[(2-methoxy- ethyl)(methyl)amino]-3-pyridinyl}-3-quinoline- carbonitrile 213 ethyl 1-{5-[4-({3-chloro-253-255 624.2 109 4-[(1-methyl-1H- (M + H) + imidazol-2-yl)sulfanyl]-phenyl}amino)-3-cyano-7- quinolinyl]-2-pyridinyl}-4-piperidinecarboxylate 214 4-({3-chloro-4-[(1- 178-180 568.2 109methyl-1H-imidazol-2- (M + H) + yl)sulfanyl)phenyl}amino)-7-[6-(4-hydroxy-1- piperidinyl)-3-pyridinyl)- 3-quinolinecarbonitrile215 4-({3-chloro-4-[(1- 239-241 597.2 109 methyl-1H-imidazol-2- (M +H) + yl)sulfanyl)phenyl}amino)- 7-{6-[4-(2-hydroxy-ethyl)-1-piperazinyl)-3- pyridinyl}-3-quinoline- carbonitrile 2164-({3-chloro-4-[(1-  228 542.3 1 methyl-1H-imidazol-2- (dec) (M + H) +yl)sulfanyl)phenyl}amino)- 7-{6-[(2-hydroxy- ethyl)(methyl)amino]-3-pyridinyl}-3-quinoline- carbonitrile 217 4-({3-chloro-4-[(1- 160-163611.3 106 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl)phenyl}amino)-7-(5-{[4-(2-hyduoxy- ethyl)-1-piperazinyl]- methyl}-2-pyridinyl)-3-quinolinecarbonitrile 218 4-(2,4-dichloro-5- 190-192 532,  41methoxyanilino)-7-{4-[(4- 534 methyl-1-piperazinyl)]- (M + H) +phenyl}-3-quinoline- carbonitrile 219 4-({3-chloro-4-[(1- 220-222 584.13106 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-(5-thiomorpholinyl- methyl)-2-pyridinyl]-3- quinolinecarbonitrile 2204-({3-chloro-4-[(1- 192-195 595.58 109 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{6-[(4-ethyl-1- piperazinyl)methyl]-3-pyridinyl}-3-quinoline- carbonitrile 221 4-({3-chloro-4-[(1- 228-230581.2 109 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-{6-[(4-methyl-1- piperazinyl)methyl]-3- pyridinyl}-3-quinoline-carbonitrile 222 4-({3-chloro-4-[(1- >250 497.41 110methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-(6-formyl-3-pyridinyl)- 3-quinoline-carbonitrile 2234-({3-chloro-4-[(1- 242-244 580.2 109 methyl-1H-imidazol-2- (M − H) −yl)sulfanyl)phenyl}amino)- 7-{6-[(4-hydroxy-1- piperidinyl)methyl]-3-pyridinyl}-3-quinoline- carbonitrile 224 4-({3-chloro-4-[(1- 246-248565.94 109 methyl-1H-imidazol-2- (M + H) + yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinyl- methyl)-3-pyridinyl]-3- quinolinecarbonitrile 2254-({3-chloro-4-[(1- 225-227 609.94  41 methyl-1H-imidazol-2- (M + H) +yl)sulfanyl]phenyl}amino)- 7-{6-[(4-isopropyl-1- piperazinyl)methyl)-3-pyridinyl}-3-quinoline- carbonitrile 226 4-(2,4-dichloro-5- 140-143523.0  41 methoxyanilino)-7-[1- (M + H) methyl-2-(4-morpholinyl-methyl)-1H-imidazol-5- yl]-3-quinolinecarbonitrile 2274-(2,4-dichloro-5- 156-159 536.1  41 methoxyanilino)-7-{1- (M + H)methyl-2-[(4-methyl-1- piperazinyl)methyl]-1H- imidazol-5-yl}-3-quinolinecarbonitrile 228 4-(2,4-dichloro-5- 141-144 482.0, 130methoxyanilino)-7-(2- 484.0 formyl-1-methyl-1H- (M + H)imidazol-5-yl)-6- methoxy-3-quinoline- carbonitrile 2294-(2,4-dichloro-5- 256-258 554.0  41 methoxyanilino)-7-[4- (M + H)({[2-(2-pyridinyl)- ethyl]amino}methyl)phen yl]-3-quinolinecarbonitrile230 4-(2,4-dichloro-5- 130-133 562.0,  41 methoxyanilino)-7-(4-{4- 564.1(2-hydroxyethyl)-1-piper- (M + H) azinyl]methyl}phenyl)-3-quinolinecarbonitrile 231 methyl 1-{4-[3-cyano-4- 278-280 575.0,  41(2,4-dichloro-5-methoxy- 577.0 anilino)-7-quinolinyl]- (M + H)benzyl}-4-piperidine- carboxylate 232 4-(2,4-dichloro-5- 248-252 553.0, 41 methoxyanilino)-6- 555.0 methoxy-7-[1-methyl-2- (M + H)(4-morpholinylmethyl)- 1H-imidazol-5-yl]-3- quinolinecarbonitrile 2334-(2,4-dichloro-5- 234-236 566.0,  41 methoxyanilino)-6- 568.0methoxy-7-{1-methyl-2- (M + H) [(4-methyl-1-piper- azinyl)methyl]-1H-imidazol-5-yl}-3- quinolinecarbonitrile 234 4-(2-chloro-5-methoxy-4-140-143 499.1,  26 methylanilino)-7-[4-(4- 501.0morpholinylmethyl)phenyl]- (M + H) 3-quinolinecarbonitrile 2354-(2-chloro-4-fluoro-5- 174-178 503.0,  26 methoxyanilino)-7-[4-(4-505.0 morpholinylmethyl)phenyl]- (M + H) 3-quinolinecarbonitrile 2364-(2-chloro-5- 160-163 485.0,  26 methoxyanilino)-7-[4-(4- 487.1morpholinylmethyl)phenyl]- (M + H) 3-quinolinecarbonitrile 2371-{4-[3-cyano-4-(2,4-  248 560.9 100 dichloro-5-methoxy- (M + H)anilino)-7-quinolinyl]- benzyl}-4-piperidine- carboxylic acid

Representative compounds of Formula I of the invention may also beprepared by the following combinatorial procedures.

COMBINATORIAL PREPARATION OF EXAMPLE 1354-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile

Step A: To a mixture of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-iodo-3-quinolinecarbonitrile(846 mg, 1.8 mmol), 4-formylbenzeneboronic acid (540 mg, 3.6 mmol) andsodium carbonate (954 mg, 9 mmol) in ethylene glycol dimethyl ether (20mL) and water (10 mL) was added tetrakis(triphenylphosphine)palladium(207 mg, 10 mol %). The resulting mixture was heated at 85° C. for 6-18hours. The mixture was cooled to room temperature and concentrated. Theresidue was suspended in N,N′-dimethylformamide (24 mL) and filtered.The filtrate containing4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrilewas used directly in Step B.

Step B: A solution of4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrilein N,N′-dimethylformamide (0.15 mmol, 2 mL, {fraction (1/12)} th of thesolution prepared in Step A) was diluted with N,N′-dimethylformamide (4mL) and dichloromethane (18 mL), then 1-methylpiperazine (45.5 mg, 0.45mmol) and acetic acid (90 uL, 1.5 mmol) were added. The mixture wasshaken on an orbital shaker for 10-30 minutes, then sodiumcyanoborohydride (63 mg, 1.0 mmol) was added and shaking continued for12-16 hours. The solvent was evaporated and the product purified bysemi-preparative RP-HPLC to give4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile(22 mg).

Semi-preparative Reverse Phase (RP)-HPLC conditions:

Sample dissolved in methanol (1.5 mL);

Column: YMC Pro C18 20 mm×50 mm 5 um;

Solvent A: 0.02% trifluoroacetic acid/water; Solvent B: 0.02%trifluoroacetic acid/acetonitrile;

Gradient: Time 0 min: 95% A; 2 min: 95% A; 15 min: 10% A; 16 min: 10% A;

Flow rate 22.5 mL/min;

Detection: 254 nm DAD.

Examples 238-271 in Table 5 were synthesized using4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-iodo-3-quinolinecarbonitrilewith 4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,2-formylfuran-5-boronic acid, 5-formyl-2-thiophene boronic acid,2-bromo-5-formylpyridine* and 4-hydroxypiperidine,N,N-dimethylethylenediamine, 4-(1-pyrrolidinyl)-piperidine,4-(aminomethyl)pyridine, dimethylamine, morpholine, ethanolamine,1-methylpiperazine, N-(3-aminopropyl)morpholine, piperidine,1-ethylpiperazine and 1-(2-hydroxyethyl)piperazine and following thecombinatorial procedure outlined for Example 135:

*Note: 2-Bromo-5-formylpyridine was coupled with7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrileunder the following conditions. A mixture of7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile(942 mg, 2 mmol), 2-bromo-5-formylpyridine (372 mg, 2 mmol),hexamethylditin (655 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(440 mg, 0.4 mmol) and lithium chloride (250 mg, 6 mmol) in dioxane (20mL) was heated to 110° C. for 4 hours. The mixture was cooled to roomtemperature and concentrated. The residue was suspended inN,N′-dimethylformamide (24 mL) and filtered. The filtrate was useddirectly in Step B.

TABLE 5

LCMS Retent. Theoretical Exptl. Time Example Ar R1R2N (M + H)+ (M + H)+min. 135 1,4-phenyl 1-methylpiperazine 580.20447 580.20344 1.86 2381,4-phenyl N,N-dimethylethylenediamine 568.20447 568.20373 1.71 2391,4-phenyl 4-(1-pyrrolidinyl)-piperidine 634.25142 634.25036 1.74 2401,4-phenyl 4-(aminomethyl)pyridine 588.17317 588.17206 1.8  2411,4-phenyl dimethylamine 525.16227 525.16159 1.85 243 1,4-phenylethanolamine 541.15719 541.15618 1.81 244 1,4-phenylN-(3-aminopropyl)morpholine 624.23068 624.22949 1.72 245 1,4-phenyl1-ethylpiperazine 594.22012 594.21914 1.87 246 1,4-phenyl1-(2-hydroxyethyl)piperazine 610.21504 610.21412 1.84 247 1,3-phenyl4-hydroxypiperidine 581.18849 581.18731 1.89 248 1,3-phenylN,N-dimethylethylenediamine 568.20447 568.20383 1.75 249 1,3-phenyl4-(1-pyrrolidinyl)-piperidine 634.25142 634.25042 1.78 250 1,3-phenyl4-(aminomethyl)pyridine 588.17317 588.17203 1.84 251 1,3-phenyldimethylamine 525.16227 525.16147 1.9  252 1,3-phenyl morpholine567.17284 567.17187 1.91 253 1,3-phenyl ethanolamine 541.15719 541.156181.86 254 1,3-phenyl 1-methylpiperazine 580.20447 580.20358 1.81 2551,3-phenyl N-(3-aminopropyl)morpholine 624.23068 624.22955 1.77 2561,3-phenyl piperidine 565.19357 565.19275 2   257 1,3-phenyl1-ethylpiperazine 594.22012 594.21928 1.83 258 1,3-phenyl1-(2-hydroxyethyl)piperazine 610.21504 610.21434 1.9  259 2,5-furyl4-hydroxypiperidine 571.16775 571.16671 1.81 260 2,5-furylN,N-dimethylethylenediamine 558.18374 558.18267 1.69 261 2,5-furyl4-(1-pyrrolidinyl)-piperidine 624.23069 624.22970 1.71 262 2,5-furylethanolamine 531.13645 531.13573 1.81 263 2,5-furyl 1-methylpiperazine570.18374 570.18268 1.84 264 2,5-furyl N-(3-aminopropyl)morpholine614.20995 614.20898 1.83 265 2,5-thienyl N,N-dimethylethylenediamine574.16089 574.15973 1.73 266 2,5-thienyl 4-(1-pyrrolidinyl)-piperidine640.20784 640.20653 1.76 267 2,5-thienyl ethanolamine 547.11361547.11303 1.8  268 2,5-thienyl N-(3-aminopropyl)morpholine 630.18710630.18600 1.8  269 2,5-thienyl 1-ethylpiperazine 600.17654 600.175611.93 270 2,5-pyridyl N,N-dimethylethylenediamine 569.19972 569.198791.66 271 2,5-pyridyl N-(3-aminopropyl)morpholine 625.22593 625.225021.66

LCMS conditions: Hewlett Packard 1100 MSD; YMC ODS-AM 2.0 mm×50 mm 5 ucolumn at 23° C.; 3 μL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 4.7min: 10% A; 4.9 min: 95% A; Post time 1 min. Flow rate 1.5 mL/min;Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700; Fragmentor70 mV.

Examples 272-328 in Table 6 were synthesized using4-(2,4-dimethylanilino)-7-iodo-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzenediamine acid,2-formylfuran-5-boronic acid, 5-formyl-2-thiophene boronic acid,5-formyl-3-thiophene boronic acid and 4-hydroxypiperidine,N,N-dimethylethylenediamine, 4-(1-pyrrolidinyl)piperidine,4-(aminomethyl)pyridine, histamine, morpholine, ethanolamine,1-methylpiperzine, N-(3-aminopropyl)morpholine, piperidine,1-ethylpiperazine and 1-(2-hydroxyethyl)piperazine and following thecombinatorial procedure outlined for Example 135:

TABLE 6

HPLC Retent. Ion Time Example Ar R1R2N observed Theoretical Exptl. Min.272 1,4-phenyl 4-hydroxypiperidine [M + 2H]2+ 232.12826 232.12798 2.01273 1,4-phenyl N,N-dimethylethylenediamine [M + 2H]2+ 225.63625225.63614 1.78 274 1,4-phenyl 4-(1-pyrrolidinyl)-piperidine [M + 2H]2+258.65973 258.65933 1.82 275 1,4-phenyl 4-(aminomethyl)pyridine [M +2H]2+ 235.62060 235.62029 1.97 276 1,4-phenyl histamine [M + 2H]2+237.12605 237.12564 1.88 277 1,4-phenyl morpholine [M + 2H]2+ 225.12043225.12020 2.07 278 1,4-phenyl ethanolamine [M + 2H]2+ 212.11261212.11259 1.98 279 1,4-phenyl 1-methylpiperazine [M + 2H]2+ 231.63625231.63594 2.02 280 1,4-phenyl N-(3-aminopropyl)morpholine [M + 2H]2+253.64936 253.64883 1.81 281 1,4-phenyl piperidine [M + 2H]2+ 224.13080224.13051 2.14 282 1,4-phenyl 1-ethylpiperazine [M + 2H]2+ 238.64408238.64370 2.02 283 1,4-phenyl 1-(2-hydroxyethyl)piperazine [M + 2H]2+246.64153 246.64104 1.98 284 1,3-phenyl 4-hydroxypiperidine [M + 2H]2+232.12826 232.12800 2.04 285 1,3-phenyl N,N-dimethylethylenediamine [M +2H]2+ 225.63625 225.63612 1.83 286 1,3-phenyl4-(1-pyrrolidinyl)-piperidine [M + 2H]2+ 258.65973 258.65934 1.85 2871,3-phenyl 4-(aminomethyl)pyridine [M + 2H]2+ 235.62060 235.62027 2.08288 1,3-phenyl histamine [M + 2H]2+ 237.12605 237.12565 1.86 2891,3-phenyl morpholine [M + 2H]2+ 225.12043 225.12021 2.06 290 1,3-phenylethanolamine [M + 2H]2+ 212.11261 212.11254 1.96 291 1,3-phenyl1-methylpiperazine [M + 2H]2+ 231.63625 231.63591 2.11 292 1,3-phenylN-(3-aminopropyl)morpholine [M + 2H]2+ 253.64936 253.64931 1.96 2931,3-phenyl piperidine [M + 2H]2+ 224.13080 224.13055 2.25 294 1,3-phenyl1-ethylpiperazine [M + 2H]2+ 238.64408 238.64375 2.13 295 1,3-phenyl1-(2-hydroxyethyl)piperazine [M + 2H]2+ 246.64153 246.64109 2.1  2962,5-furyl 4-hydroxypiperidine [M + 2H]2+ 227.11789 227.11787 1.96 2972,5-furyl N,N-dimethylethylenediamine [M + 2H]2+ 220.62588 220.625791.8  298 2,5-furyl 4-(1-pyrrolidinyl)-piperidine [M + 2H]2+ 253.64936253.64889 1.79 299 2,5-furyl 4-(aminomethyl)pyridine [M + 2H]2+230.61023 230.60992 1.87 300 2,5-furyl histamine [M + 2H]2+ 232.11568232.11548 1.73 301 2,5-furyl morpholine [M + 2H]2+ 220.11007 220.110221.99 302 2,5-furyl ethanolamine [M + Na]1+ 435.17915 435.17826 2   3032,5-furyl 1-methylpiperazine [M + 2H]2+ 226.62588 226.62557 1.99 3042,5-furyl piperidine [M + 2H]2+ 219.12043 219.12034 2.12 305 2,5-furyl1-ethylpiperazine [M + 2H]2+ 233.63371 233.63350 2.01 306 2,5-furyl1-(2-hydroxyethyl)piperazine [M + 2H]2+ 241.63117 241.63072 1.99 3072,5-thienyl 4-hydroxypiperidine [M + 2H]2+ 235.10647 235.10634 2.04 3082,5-thienyl N,N-dimethylethylenediamine [2M + H]1+ 911.43602 911.435831.84 309 2,5-thienyl 4-(1-pyrrolidinyl)-piperidine [M + 2H]2+ 261.63794261.63756 1.86 310 2,5-thienyl 4-(aminomethyl)pyridine [M + 2H]2+238.59881 238.59845 1.95 311 2,5-thienyl histamine [M + 2H]2+ 240.10426240.10388 1.83 312 2,5-thienyl morpholine [M + 2H]2+ 228.09864 228.098632.05 313 2,5-thienyl ethanolamine [M + 2H]2+ 215.09082 215.09083 2.06314 2,5-thienyl 1-methylpiperazine [M + 2H]2+ 234.61446 234.61417 2.17315 2,5-thienyl 1-ethylpiperazine [M + 2H]2+ 241.62229 241.62195 2.18316 2,5-thienyl 1-(2-hydroxyethyl)piperazine [M + 2H]2+ 249.61974249.61929 2.13 317 2,4-thienyl 4-hydroxypiperidine [M + 2H]2+ 235.10647235.10622 2.05 318 2,4-thienyl N,N-dimethylethylenediamine [M + 2H]2+228.61446 228.61431 1.75 319 2,4-thienyl 4-(1-pyrrolidinyl)-piperidine[M + 2H]2+ 261.63794 261.63739 1.96 320 2,4-thienyl4-(aminomethyl)pyridine [M + 2H]2+ 238.59881 238.59848 2   3212,4-thienyl histamine [M + 2H]2+ 240.10426 240.10389 1.93 3222,4-thienyl morpholine [M + 2H]2+ 228.09864 228.09856 2.08 3232,4-thienyl ethanolamine [M + 2H]2+ 215.09082 215.09055 2.06 3242,4-thienyl 1-methylpiperazine [M + 2H]2+ 234.61446 234.61414 2.12 3252,4-thienyl N-(3-aminopropyl)morpholine [M + 2H]2+ 256.62757 256.627111.96 326 2,4-thienyl piperidine [M + 2H]2+ 227.10901 227.10880 2.18 3272,4-thienyl 1-ethylpiperazine [M + 2H]2+ 241.62229 241.62185 2.15 3282,4-thienyl 1-(2-hydroxyethyl)piperazine [M + 2H]2+ 249.61974 249.619302.12

Examples 329-350 in Table 7 were synthesized using4-(4-bromo-2-chloro-6-methylanilino)-7-iodo-3-quinolinecarbonitrile with2-formylfuran-5-boronic acid and 5-formyl-2-thiophene boronic acid and4-hydroxypiperidine, N,N-dimethylethylenediamine,4-(1-pyrrolidinyl)-piperidine, 4-(aminomethyl)pyridine, histamine,morpholine, ethanolamine, 1-methylpiperazine,N-(3-aminopropyl)morpholine, piperidine, 1-ethylpiperazine and1-(2-hydroxyethyl)piperazine and following the combinatorial procedureoutlined for Example 135:

TABLE 7

HPLC Ion Ret. Example Ar R1R2N observed Theoretical Exptl. time 3292,5-furyl 4-hydroxypiperidine [M + 2H]2+  276.04584  276.04572 2.37 3302,5-furyl N,N-dimethylethylenediamine [M + 2H]2+  269.55383  269.553432.17 331 2,5-furyl 4-(1-pyrrolidinyl)-piperidine [M + 3H]3+  202.05396 202.05603 2.19 332 2,5-furyl 4-(aminomethyl)pyridine [M + 2H]2+ 279.53818  279.53778 2.19 333 2,5-furyl histamine [M + 2H]2+  281.04363 281.04341 2.3  334 2,5-furyl morpholine [M + 2H]2+  269.03801 269.03780 2.4  335 2,5-furyl ethanolamine [2M + H]1+ 1021.098921021.09798 2.57 336 2,5-furyl 1-methylpiperazine [M + 2H]2+  275.55383 275.55330 2.58 337 2,5-furyl N-(3-aminopropyl)morpholine [M + 2H]2+ 297.56694  297.56624 2.44 338 2,5-furyl piperidine [M + 2H]2+ 268.04838  268.04842 2.78 339 2,5-furyl 1-ethylpiperazine [M + 2H]2+ 282.56165  282.56102 2.65 340 2,5-furyl 1-(2-hydroxyethyl)piperazine[M + 2H]2+  290.55911  290.55849 2.54 341 2,5-thienyl4-hydroxypiperidine [M + 2H]2+  284.03441  284.03424 2.64 3422,5-thienyl N,N-dimethylethylenediamine [M + 2H]2+  277.54241  277.541832.43 343 2,5-thienyl 4-(1-pyrrolidinyl)-piperidine [M + 2H]2+  310.56588 310.56510 2.44 344 2,5-thienyl 4-(aminomethyl)pyridine [M + 2H]2+ 287.52676  287.52607 2.57 345 2,5-thienyl histamine [M + 2H]2+ 289.03221  289.03143 2.47 346 2,5-thienyl Morpholine [2M + H]1+1105.08452 1105.08508 2.71 347 2,5-thienyl ethanolamine [M + 2H]2+ 264.01876  264.01862 2.62 348 2,5-thienyl 1-methylpiperazine [M + 2H]2+ 283.54241  283.54177 2.67 349 2,5-thienyl N-(3-aminopropyl)morpholine[M + 2H]2+  305.55551  305.55454 2.47 350 2,5-thienyl piperidine [M +H]+  551.01  551.07  2.84

Examples 351-382 in Table 8 were synthesized using4-(4-bromo-2-chloro-6-methylanilino)-7-iodo-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid and5-formyl-3-thiophene boronic acid with 4-hydroxypiperidine,N,N-dimethylethylenediamine, 4-(1-pyrrolidinyl)-piperidine,4-(aminomethyl)pyridine, histamine, morpholine, ethanolamine,1-methylpiperazine, N-(3-aminopropyl)morpholine, piperidine,1-ethylpiperazine and 1-(2-hydroxyethyl)piperazine and following thecombinatorial procedure outlined for Example 135:

TABLE 8

HPLC Ion Ret. Example Ar R1R2N observed Theoretical Exptl. time 3511,4-phenyl 4-hydroxypiperidine [M + 3H]3+ 224.77484 224.77473 1.89 3521,4-phenyl N,N-dimethylethylenediamine [M + 2H]2+ 323.67461 323.674601.62 353 1,4-phenyl 4-(1-pyrrolidinyl)-piperidine [M + 3H]3+ 260.15013260.15025 1.67 354 1,4-phenyl morpholine [M + 2H]2+ 322.64298 322.642801.91 355 1,4-phenyl ethanolamine [M + 2H]2+ 296.62733 296.62702 1.81 3561,4-phenyl 1-methylpiperazine [M + 3H]3+ 224.11883 224.11891 1.91 3571,4-phenyl N-(3-aminopropyl)morpholine [M + 3H]3+ 253.46964 253.469291.93 358 1,4-phenyl piperidine [M + 3H]3+ 214.11157 214.11140 2.1  3591,4-phenyl 1-ethylpiperazine [M + 3H]3+ 233.46260 233.46228 1.94 3601,4-phenyl 1-(2-hydroxyethyl)piperazine [M + 3H]3+ 244.12588 244.125461.87 361 1,3-phenyl 4-hydroxypiperidine [M + 3H]3+ 224.77484 224.774701.98 362 1,3-phenyl N,N-dimethylethylenediamine [M + H]+  646.34  646.3   1.73 363 1,3-phenyl 4-(1-pyrrolidinyl)-piperidine [M + 3H]3+260.15013 260.15000 1.77 364 1,3-phenyl 4-(aminomethyl)pyridine [M +3H]3+ 229.43130 229.43129 1.89 365 1,3-phenyl histamine [M + 3H)3+231.43857 231.43849 1.75 366 1,3-phenyl morpholine [M + 2H]2+ 322.64298322.64197 2   367 1,3-phenyl ethanolamine [M + 2H]2+ 296.62733 296.627171.92 368 1,3-phenyl 1-methylpiperazine [M + 3H]3+ 224.11883 224.118592.02 369 1,3-phenyl N-(3-aminopropyl)morpholine [M + 3H]3+ 253.46964253.46924 1.75 370 1,3-phenyl piperidine [M + 3H]3+ 214.11157 214.111392.2  371 1,3-phenyl 1-ethylpiperazine [M + 3H]3+ 233.46260 233.462232.05 372 1,3-phenyl 1-(2-hydroxyethyl)piperazine [M + 3H]3+ 244.12588244.12495 1.98 373 2,4-thienyl N,N-dimethylethylenediamine [M + 3H]3+220.08978 220.08941 1.64 374 2,4-thienyl 4-(1-pyrrolidinyl)-piperidine[M + H]1+  790.34869 790.34843 1.67 375 2,4-thienyl4-(aminomethyl)pyridine [M + 3H]3+ 233.40225 233.40173 1.8  3762,4-thienyl histamine [M + H]1+  704.21399 704.21442 1.98 3772,4-thienyl morpholine [M + 2H]2+ 328.59940 328.59852 1.95 3782,4-thienyl 1-methylpiperazine [M + H]1+  682.25479 682.25389 2.04 3792,4-thienyl N-(3-aminopropyl)morpholine [M + H]1+  770.30722 770.307751.67 380 2,4-thienyl piperidine [M + 3H]3+ 218.08252 218.08236 2.14 3812,4-thienyl 1-ethylpiperazine [M + 3H]3+ 237.43355 237.43272 2.11 3822,4-thienyl 1-(2-hydroxyethyl)piperazine [M + 3H]3+ 248.09682 248.095842.01

Examples 383-421 in Table 9 were synthesized using4-(3-chloro-4-phenoxyphenylamino)-7-iodo-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,2-formylfuran-5-boronic acid, 5-formyl-2-thiophene boronic acid,5-formyl-3-thiophene boronic acid, 2-bromo-5-formylpyridine* and4-hydroxypiperidine, N,N-dimethylethylenediamine,4-(1-pyrrolidinyl)-piperidine, 4-(aminomethyl)pyridine, histamine,morpholine, ethanolamine, 1-methylpiperazine,N-(3-aminopropyl)morpholine, piperidine, 1-ethylpiperazine and1-(2-hydroxyethyl)piperazine and following the combinatorial procedureoutlined for Example 135.

*Note: 2-Bromo-5-formylpyridine was coupled with7-bromo-4-(3-chloro-4-phenoxyphenylamino)-3-quinolinecarbonitrile underthe same conditions that were used for coupling with7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile.

TABLE 9

LCMS Theoretical Exptl. Retention Example Ar R1R2N (M + 2H)2+ (M + 2H)2+time 383 1,4-phenyl N-(3-aminopropyl)morpholine 302.62733 302.62675 2.13384 1,4-phenyl 1-ethylpiperazine 287.62205 287.62155 2.27 385 1,4-phenyl1-(2-hydroxyethyl)piperazine 295.61950 295.61904 2.24 386 1,3-phenylN,N-dimethylethylenediamine 274.61422 274.61410 2.14 387 1,3-phenyl4-(1-pyrrolidinyl)-piperidine 307.63770 307.63710 2.17 388 1,3-phenyl4-(aminomethyl)pyridine 284.59857 284.59810 2.21 389 1,3-phenylN-(3-aminopropyl)morpholine 302.62733 302.62681 2.14 390 1,3-phenyl1-ethylpiperazine 287.62205 287.62152 2.28 391 2,5-furyl4-hydroxypiperidine 276.09586 276.09602 2.27 392 2,5-furylN,N-dimethylethylenediamine 269.60385 269.60387 2.12 393 2,5-furyl4-(1-pyrrolidinyl)-piperidine 302.62733 302.62666 2.13 394 2,5-furyl4-(aminomethyl)pyridine 279.58820 279.58772 2.20 395 2,5-furyl histamine281.09365 281.09374 2.10 396 2,5-furyl morpholine 269.08804 269.088252.30 397 2,5-furyl ethanolamine 533.13509¹ 533.13339¹ 2.24 398 2,5-furyl1-methylpiperazine 275.60385 275.60331 2.24 399 2,5-furylN-(3-aminopropyl)morpholine 297.61696 297.61630 2.10 400 2,5-furylpiperidine 535.18953² 535.19000² 2.11 401 2,5-furyl 1-ethylpiperazine282.61168 282.61102 2.28 402 2,5-furyl 1-(2-hydroxyethyl)piperazine290.60914 290.60843 2.24 403 2,5-thienyl N,N-dimethylethylenediamine277.59243 277.59255 2.13 404 2,5-thienyl 4-(1-pyrrolidinyl)-piperidine310.61591 310.61514 2.17 405 2,5-thienyl 4-(aminomethyl)pyridine287.57678 287.57619 2.24 406 2,5-thienyl morpholine 553.14² 553.01² 2.37407 2,5-thienyl 1-methylpiperazine 283.59243 283.59182 2.30 4082,5-thienyl 1-ethylpiperazine 290.60026 290.59946 2.35 409 3,5-thienyl4-hydroxypiperidine 284.08444 284.08400 2.27 410 3,5-thienylN,N-dimethylethylenediamine 277.59243 277.59236 2.08 411 3,5-thienyl4-(1-pyrrolidinyl)-piperidine 310.61591 310.61493 2.10 412 3,5-thienyl4-(aminomethyl)pyridine 287.57678 287.57610 2.11 413 3,5-thienylhistamine 289.08223 289.08147 2.13 414 3,5-thienyl morpholine 553.14595²553.14540² 2.30 415 3,5-thienyl ethanolamine 549.11224¹ 549.11151¹ 2.23416 3,5-thienyl 1-methylpiperazine 283.59243 283.59182 2.28 4173,5-thienyl N-(3-aminopropyl)morpholine 305.60554 305.60459 2.09 4183,5-thienyl piperidine 276.08698 276.08710 2.41 419 3,5-thienyl1-ethylpiperazine 290.60026 290.59949 2.30 420 3,5-thienyl1-(2-hydroxyethyl)piperazine 298.59771 298.59690 2.25 421 2,4-pyridylN-(3-aminopropyl)morpholine 303.12495 303.12490 2.10 ¹[M + Na]+ ²[M +H]+

Examples 422-464 in Table 10 were synthesized using4-(3-chloro-4-phenylsulfanylphenylamino)-7-iodo-3-quinolinecarbonitrilewith 4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,2-formylfuran-5-boronic acid, 5-formyl-2-thiophene boronic acid,5-formyl-3-thiophene boronic acid and 4-hydroxypiperidine,N,N-dimethylethylenediamine, 4-(1-pyrrolidinyl)-piperidine,4-(aminomethyl)pyridine, histamine, morpholine, ethanolamine,1-methylpiperazine, N-(3-aminopropyl)morpholine, piperidine,1-ethylpiperazine and 1-(2-hydroxyethyl)piperazine and following thecombinatorial procedure outlined for Example 135:

TABLE 10

LCMS Theoretical Exptl. Retention Example Ar R1R2N (M + 2H)2+ (M + 2H)2+time 422 1,4-phenyl 4-hydroxypiperidine 577.18234¹ 577.18295¹ 2.87 4231,4-phenyl 4-(aminomethyl)pyridine 292.58715 292.58655 2.74 4241,4-phenyl histamine 294.09260 294.09187 2.61 425 1,4-phenyl morpholine282.08698 282.08626 2.91 426 1,4-phenyl ethanolamine 269.07916 269.078612.84 427 1,4-phenyl 1-methylpiperazine 288.60280 288.60206 2.82 4281,4-phenyl N-(3-aminopropyl)morpholine 310.61591 310.61527 2.64 4291,4-phenyl 1-ethylpiperazine 295.61062 295.60985 2.37 430 1,4-phenyl1-(2-hydroxyethyl)piperazine 303.60808 303.60740 2.34 431 1,3-phenyl4-hydroxypiperidine 289.09481 289.09417 2.41 432 1,3-phenylN,N-dimethylethylenediamine 282.60280 282.60225 2.21 433 1,3-phenyl4-(1-pyrrolidinyl)-piperidine 315.62627 315.62597 2.23 434 1,3-phenylethanolamine 179.72186³ 179.72230³ 2.38 435 1,3-phenylN-(3-aminopropyl)morpholine 310.61591 310.61550 2.24 436 1,3-phenyl1-(2-hydroxyethyl)piperazine 303.60808 303.60778 2.35 437 2,5-furyl4-hydroxypiperidine 567.16160¹ 567.16421¹ 2.38 438 2,5-furylN,N-dimethylethylenediamine 277.59243 277.59188 2.61 439 2,5-furyl4-(1-pyrrolidinyl)-piperazine 620.22¹ 620.12¹ 2.64 440 2,5-furyl4-(aminomethyl)pyridine 287.57678 287.57642 2.74 441 2,5-furyl histamine577.15¹ 577.06¹ 2.61 442 2,5-furyl morpholine 553.14595¹ 553.14817¹ 2.94443 2,5-furyl ethanolamine 176.38162² 176.38187² 2.84 444 2,5-furyl1-methylpiperazine 283.59243 283.59207 2.81 445 2,5-furylN-(3-aminopropyl)morpholine 305.60554 305.60518 2.21 446 2,5-furyl1-ethylpiperazine 580.19324¹ 580.19320¹ 2.37 447 2,5-thienylN,N-dimethylethylenediamine 570.15474¹ 570.15362¹ 2.24 448 2,5-thienyl4-(1-pyrrolidinyl)-piperidine 636.20169¹ 636.20071¹ 2.24 449 2,5-thienylmorpholine 569.12311¹ 569.12237¹ 2.47 450 2,5-thienyl 1-methylpiperazine582.15474¹ 582.15410¹ 2.44 451 2,5-thienyl N-(3-aminopropyl)morpholine626.18096¹ 626.18051¹ 2.24 452 2,5-thienyl 1-ethylpiperazine 298.58884298.58852 2.47 453 3,5-thienyl 4-hydroxypiperidine 583.13876¹ 583.13778¹2.37 454 3,5-thienyl N,N-dimethylethylenediamine 285.58101 285.580622.21 455 3,5-thienyl 4-(1-pyrrolidinyl)-piperidine 318.60449 318.604152.21 456 3,5-thienyl 4-(aminomethyl)pyridine 295.56536 295.56502 2.27457 3,5-thienyl histamine 297.07081 297.07052 2.20 458 3,5-thienylmorpholine 285.06519 285.06482 2.41 459 3,5-thienyl ethanolamine543.10746¹ 543.10928¹ 2.34 460 3,5-thienyl 1-methylpiperazine 582.15475¹582.15585¹ 2.41 461 3,5-thienyl N-(3-aminopropyl)morpholine 313.59412313.59399 2.21 462 3,5-thienyl piperidine 284.07556 284.07532 2.47 4633,5-thienyl 1-ethylpiperazine 298.58884 298.58842 2.41 464 3,5-thienyl1-(2-hydroxyethyl)piperazine 612.16531¹ 612.16497¹ 2.38 ¹[M + H]+ ²[M +3H]3+

Examples 465-476 in Table 11 were synthesized using4-{[3-chloro-4-(3-furylmethyl)phenyl]amino})-7-(4-formylphenyl)-3-quinolinecarbonitrilewith 4-hydroxypiperidine, N,N-dimethylethylenediamine,4-(1-pyrrolidinyl)-piperidine, 4-aminomethyl)pyridine, histamine,morpholine, ethanolamine, 1-methylpiperazine,N-(3-aminopropyl)morpholine, piperidine, 1-ethylpiperazine and1-(2-hydroxyethyl)piperazine and following the combinatorial procedureoutlined for Example 135.

TABLE 11

LCMS Theoretical Exptl. Ret. Example Ar R1R2N (M + H)+ (M + H)+ time 4651,4-phenyl 4-hydroxypiperidine 549.2 549.1 2.54 466 1,4-phenylN,N-dimethylethylenediamine 536.2 536.1 2.36 467 1,4-phenyl4-(1-pyrrolidinyl)-piperidine 602.3 602.3 2.34 468 1,4-phenyl4-(aminomethyl)pyridine 556.2 556.1 2.41 469 1,4-phenyl histamine 559.2559.1 2.34 470 1,4-phenyl morpholine 535.2 535.1 2.58 471 1,4-phenylethanolamine 509.2 509.1 2.52 472 1,4-phenyl 1-methylpiperazine 548.2548.1 2.47 473 1,4-phenyl N-(3-aminopropyl)morpholine 592.2 592.2 2.34474 1,4-phenyl piperidine 533.2 533.1 2.67 475 1,4-phenyl1-ethylpiperazine 562.2 562.1 2.48 476 1,4-phenyl1-(2-hydroxyethyl)piperazine 578.2 578.3 2.44

Examples 477-510 in Table 12 were synthesized using4-{[4-(3-furylmethyl)phenyl]amino}-7-iodo-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,5-formyl-3-thiophene boronic acid, 2-bromo-5-formylpyridine* and4-hydroxypiperidine, N,N-dimethylethylenediamine,4-(1-pyrrolidinyl)-piperidine, 4-(aminomethyl)pyridine, histamine,morpholine, ethanolamine, 1-methylpiperazine,N-(3-aminopropyl)morpholine, piperidine, 1-ethylpiperazine and1-(2-hydroxyethyl)piperazine and following the combinatorial procedureoutlined for Example 135.

*Note: 2-Bromo-5-formylpyridine was coupled with7-bromo-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile underthe following conditions. A mixture of7-bromo-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile (808mg, 2 mmol), 2-bromo-5-formylpyridine (372 mg, 2 mmol), hexamethylditin(655 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (440 mg, 0.4mmol) and lithium chloride (250 mg, 6 mmol) in dioxane (20 mL) washeated to 110° C. for 4 hours. The mixture was cooled to roomtemperature and concentrated. The residue was suspended inN,N′-dimethylformamide (24 mL) and filtered. The filtrate was useddirectly in Step B.

TABLE 12

LCMS Theoretical Exptl. Ret. Example Ar R1R2N (M + H)+ (M + H)+ time 4771,4-phenyl 4-(aminomethyl)pyridine 522.2 522.1 2.15 478 1,4-phenylhistamine 525.2 525.2 2.07 479 1,4-phenyl morpholine 501.2 501.1 2.32480 1,4-phenyl ethanolamine 475.2 475.2 2.27 481 1,4-phenyl1-methylpiperazine 514.3 514.2 2.24 482 1,4-phenyl piperidine 499.2499.2 2.40 483 1,4-phenyl 1-ethylpiperazine 528.3 528.2 2.27 4841,4-phenyl 1-(2-hydroxyethyl)piperazine 544.3 544.3 2.21 485 1,3-phenyl4-hydroxypiperidine 515.2 515.2 2.32 486 1,3-phenylN,N-dimethylethylenediamine 502.3 502.2 2.10 487 1,3-phenyl4-(1-pyrrolidinyl)-piperidine 568.3 568.5 2.14 488 1,3-phenyl4-(aminomethyl)pyridine 522.2 522.1 2.20 489 1,3-phenyl histamine 525.2525.2 2.11 490 1,3-phenyl morpholine 501.2 501.2 2.34 491 1,3-phenylethanolamine 475.2 475.2 2.28 492 1,3-phenyl 1-methylpiperazine 514.3514.2 2.28 493 1,3-phenyl N-(3-aminopropyl)morpholine 558.3 558.3 2.11494 1,3-phenyl 1-ethylpiperazine 528.3 528.2 2.30 495 1,3-phenyl1-(2-hydroxyethyl)piperazine 544.3 544.2 2.24 496 2,5-pyridyl4-hydroxypiperidine 516.2 516.5 2.22 497 2,5-pyridylN,N-dimethylethylenediamine 503.3 503.5 2.04 498 2,5-pyridylethanolamine 476.2 476.5 2.20 499 2,5-pyridylN-(3-aminopropyl)morpholine 559.3 559.7 2.03 500 2,5-pyridyl1-(2-hydroxyethyl)piperazine 545.3 545.5 2.20 501 3,5-thienyl4-hydroxypiperidine 521.2 521.1 1.97 502 3,5-thienyl4-(1-pyrrolidinyl)-piperidine 574.3 574.5 1.83 503 3,5-thienyl4-(aminomethyl)pyridine 528.2 528.1 1.88 504 3,5-thienyl morpholine507.2 507.0 1.97 505 3,5-thienyl ethanolamine 481.2 481.0 1.94 5063,5-thienyl 1-methylpiperazine 520.2 520.1 2.00 507 3,5-thienylN-(3-aminopropyl)morpholine 564.2 564.4 1.84 508 3,5-thienyl piperidine505.2 505.1 2.04 509 3,5-thienyl 1-ethylpiperazine 534.2 534.2 2.01 5103,5-thienyl 1-(2-hydroxyethyl)piperazine 550.2 550.4 1.97

Examples 511-535 in Table 13 were synthesized using4-(2,4-dichloro-5-methoxyanilino)-7-iodo-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,2-formylfuran-5-boronic acid, 5-formyl-2-thiophene boronic acid,2-bromo-5-formylpyridine* and 4-hydroxypiperidine, histamine,dimethylethylenediamine, 4-(1-pyrrolidinyl)-piperidine,4-(aminomethyl)pyridine, ethanolamine, N-(3-aminopropyl)morpholine,piperidine, 1-ethylpiperazine and 1-(2-hydroxyethyl)piperazine andfollowing the combinatorial procedure outlined for Example 135.

*Note: 2-Bromo-5-formylpyridine was coupled with7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile underthe following conditions. A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (942mg, 2 mmol), 2-bromo-5-formylpyridine (372 mg, 2 mmol), hexamethylditin(655 mg, 2 mmol), tetrakis(triphenylphlosphine)palladium (440 mg, 0.4mmol) and lithium chloride (250 mg, 6 mmol) in dioxane (20 mL) washeated to 110° C. for 4 hours. The mixture was cooled to roomtemperature and concentrated. The residue was suspended inN,N′-dimethylformamide (24 mL) and filtered. The filtrate was useddirectly in Step B.

TABLE 13

LCMS Theoretical Exptl. Ret. Example Ar R1R2N (M + H)+ (M + H)+ time 5111,4-phenyl 4-(1-pyrrolidinyl)-piperidine 586.2 586.1 2.17 512 1,4-phenyl4-(aminomethyl)pyridine 540.1 540   2.24 513 1,4-phenyl histamine 543.2543.1 2.11 514 1,4-phenyl ethanolamine 493.1 493.1 2.34 515 1,4-phenylN-(3-aminopropyl)morpholine 576.2 576.1 2.14 516 2,5-furyl4-hydroxypiperidine 523.1 523.1 2.01 517 2,5-furylN,N-dimethylethylenediamine 510.2 510.1 1.88 518 2,5-furyl4-(1-pyrrolidinyl)-piperidine 576.2 576.1 1.88 519 2,5-furyl4-(aminomethyl)pyridine 530.1 530   1.93 520 2,5-furyl histamine 533.1533   1.85 521 2,5-furyl ethanolamine 483.1 483.1 1.98 522 2,5-furylN-(3-aminopropyl)morpholine 566.2 566.1 1.87 523 2,5-furyl piperidine507.1 507.1 2.14 524 2,5-furyl 1-ethylpiperazine 536.2 536.1 2.04 5252,5-thienyl 4-(1-pyrrolidinyl)-piperidine 592.2 592   1.92 5262,5-thienyl 1-ethylpiperazine 552.1 552   2.11 527 2,4-thienylN,N-dimethylethylenediamine 526.1 526.1 1.88 528 2,4-thienyl4-(aminomethyl)pyridine 546.1 546   1.93 529 2,4-thienyl histamine 549.1549   1.87 530 2,5-pyrinyl 4-hydroxypiperidine 534.2 534.1 2   5312,5-pyridyl N,N-dimethylethylenediamine 521.2 521.1 1.84 532 2,5-pyridyl4-(1-pyrrolidinyl)-piperidine 587.2 587.2 1.87 533 2,5-pyridylethanolamine 494.1 494.1 1.98 534 2,5-pyridylN-(3-aminopropyl)morpholine 577.2 577.2 1.84 535 2,5-pyridyl1-(2-hydroxyethyl)piperazine 563.2 563.1 1.98

Examples 536-567 in Table 14 were synthesized using7-iodo-4-(3,4,5-trimethyoxyanilino)-3-quinolinecarbonitrile with4-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,2-formylfuran-5-boronic acid, 2-bromo-5-formylpyridine*,5-formyl-2-thiophene boronic acid, 5-formyl-3-thiophene boronic acid4-hydroxypiperidine, N,N-dimethylethylenediamine,4-(1-pyrrolidinyl)-piperidine, 4-(aminomethyl)pyridine, histamine,morpholine, ethanolamine, 1-methylpiperazine,N-(3-aminopropyl)morpholine, piperidine, 1-ethylpiperazine and1-(2-hydroxyethyl)piperazine and following the combinatorial procedureoutlined for Example 135.

*Note: 2-Bromo-5-formylpyridine was coupled with7-bromo-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile under thefollowing conditions. A mixture of7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile (942mg, 2 mmol), 2-bromo-5-formylpyridine (372 mg, 2 mmol), hexamethylditin(655 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (440 mg, 0.4mmol) and lithium chloride (250 mg, 6 mmol) in dioxane (20 mL) washeated to 110° C. for 4 hours. The mixture was cooled to roomtemperature and concentrated. The residue was suspended inN,N′-dimethylformamide (24 mL) and filtered. The filtrate was useddirectly in Step B.

TABLE 14

HPLC Theoretical Exptl. Ret. Example Ar R1R2N (M + H)+ (M + H)+ time 5361,4-phenyl 4-hydroxypiperidine 525.3 525.2 2.22 537 1,4-phenylmorpholine 511.2 511.3 2.45 538 1,4-phenyl ethanolamine 485.2 485.3 2.35539 1,4-phenyl 1-methylpiperazine 524.3 524.3 2.36 540 1,4-phenylpiperidine 509.3 509.4 2.4  541 1,4-phenyl 1-ethylpiperazine 538.3 538.32.37 542 1,3-phenyl 4-hydroxypiperidine 525.3 525.4 2.24 543 1,3-phenylN,N-dimethylethylenediamine 512.4 512.5 1.92 544 1,3-phenyl4-(1-pyrrolidinyl)-piperidine 578.3 578.3 1.93 545 1,3-phenyl4-(aminomethyl)pyridine 532.3 532.3 2.29 546 1,3-phenyl histamine 535.3535.4 2.16 547 1,3-phenyl morpholine 511.2 511.3 2.45 548 1,3-phenylethanolamine 485.2 485.4 2.39 549 1,3-phenyl 1-methylpiperazine 524.3524.4 2.36 550 1,3-phenyl N-(3-aminopropyl)morpholine 568.3 568.4 2.16551 1,3-phenyl piperidine 509.3 509.5 2.42 552 1,3-phenyl1-(2-hydroxyethyl)piperazine 554.3 554.4 2   553 2,5-furyl4-(1-pyrrolidinyl)-piperidine 568.3 568.3 1.92 554 2,5-thienyl4-hydroxypiperidine 531.2 531.3 1.92 555 2,5-thienyl histamine 541.2541.2 1.86 556 2,5-thienyl 1-methylpiperazine 530.2 530.2 1.97 5572,5-thienyl 1-ethylpiperazine 544.2 544.4 2.16 558 2,5-thienyl1-(2-hydroxyethyl)piperazine 560.2 560.3 1.72 559 2,4-thienyl4-(aminomethyl)pyridine 538.2 538.3 1.98 560 2,4-thienyl morpholine517.2 517.2 2.15 561 2,4-thienyl ethanolamine 491.2 491.4 2.09 5622,4-thienyl 1-methylpiperazine 530.2 530.3 2.06 563 2,5-pyridinyl4-hydroxypiperidine 526.3 526.4 2.05 564 2,5-pyridinyl4-(1-pyrrolidinyl)-piperidine 579.3 579.3 1.88 565 2,5-pyridinylethanolamine 486.2 486.2 1.92 566 2,5-pyridinylN-(3-aminopropyl)morpholine 569.3 569.5 1.89 567 2,5-pyridinyl1-(2-hydroxyethyl)piperazine 555.3 555.4 2.03

The chemical names of Examples 135 and 238-567 prepared by combinatorialmeans are listed in Table 15

TABLE 15 Example # ChemicaL Names of Examples 1354-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2384-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-{([2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2394-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 2404-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2414-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{(4-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile 2434-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2444-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2454-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2464-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 2474-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-hydroxy-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 2484-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2494-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 2504-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2514-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile 2524-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 2534-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2544-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2554-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2564-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 2574-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2584-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 2594-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 2604-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 2614-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonltrile 2624-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 2634-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 2644-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 2654-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile2664-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile2674-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 2684-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile 2694-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 2704-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile2714-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile2724-(2,4-dimethylanilino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 2737-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile 2744-(2,4-dimethylanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 2754-(2,4-dimethylanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2764-(2,4-dimethylanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2774-(2,4-dimethylanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 2784-(2,4-dimethylanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2794-(2,4-dimethylanilino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2804-(2,4-dimethylanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2814-(2,4-dimethylanilino)-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 2824-(2,4-dimethylanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2834-(2,4-dimethylanilino)-7-{4-([4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 2844-(2,4-dimethylanilino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 2857-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile 2864-(2,4-dimethylanilino)-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 2874-(2,4-dimethylanilino)-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2884-(2,4-dimethylanilino)-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2894-(2,4-dimethylanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 2904-(2,4-dimethylanilino)-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 2914-(2,4-dimethylanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2924-(2,4-dimethylanilino)-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 2934-(2,4-dimethylanilino)-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 2944-(2,4-dimethylanilino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 2954-(2,4-dimethylanilino)-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 2964-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 2977-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile 2984-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 2994-(2,4-dimethylanilino)-7-[5-({[4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 3004-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 3014-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile 3024-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 303 4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1piperazinyl)methyl]-2-furyl}-3- quinolinecarbonitrile 3044-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile 3054-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3064-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 3074-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 3087-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile 3094-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 3104-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 3114-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile 3124-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile 3134-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 3144-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 3154-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 3164-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 3174-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 3187-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile 3194-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 3204(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 3214-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 3224-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl}-3-quinolinecarbonitrile 3234-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 3244-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 3254-(2,4-dimethylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 3264-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 3274-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 3284-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 3294-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3304-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 3314-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 3324-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 3334-(4-bromo-2-chloro-6-methylanilino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 3344-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile 3354-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 3364-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3374-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl]-2-furyl)-3-quinolinecarbonitrile 3384-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile 3394-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3404-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 3414-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 3424-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile343 4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 3444-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 3454-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile 3464-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile 3474-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 3484-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 3494-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile 3504-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile 3514-([3-chloro-4′-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl)amino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 3524-([3-chloro-4′-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1′-biphenyl]-4-yl]amino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3534-[(3-chloro-5-methyl-4′-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[1,1′-biphenyl]-4-yl)amino]-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 3544-{[3-chloro-5-methyl-4′-(4-morpholinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 3554-[(3-chloro-4′-{[(2-hydroxyethyl)amino]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 3564-((3-chloro-5-methyl-4′-[(4-methyl-1-piperazinyl)methyl][1,1′-biphenyl]-4-yl]amino)-7-(4-[(4-methyl-1-piperazinyl)methyl]phenyl)-3-quinolinecarbonitrile 3574-([3-chloro-5-methyl-4′-({[3-(4-morpholinyl)propyl]amino)methyl}[1,1′-biphenyl}-4-yl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino)methyl)penyl]-3-quinolinecarbonitrile 3584-([3-chloro-5-methyl-4′-(1-piperidinylmethyl)[1,1′-biphenyl]-4-yl]amino)-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 3594-({3-chloro-4′-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl)amino)-7-(4-[(4-ethyl-1-piperazinyl)methyl]phenyl)-3-quinolinecarbonitrile3604-[(3-chloro-4′-([4-(2-hydroxyethyl)-1-piperazinyl]methyl)-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(4-([4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 3614-({3-chloro-3′-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl}amino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 3624-{[3-chloro-3′-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1′-biphenyl]-4-yl]amino}-7-[3-({[2-(dimethylamino}ethyl]amino)methyl)phenyl]-3-quinolinecarbonitrile 3634-[(3-chloro-5-methyl-3′-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[1,1′-biphenyl]-4-yl}amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 3644-[(3-chloro-5-methyl-3′-{[(4-pyridinylmethyl)amino]methyl}[1,1′-biphenyl]-4-yl)amino]-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 3654-{[3-chloro-3′-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-5-methyl[1,1′-biphenyl]-4-yl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3664-{[3-chloro-5-methyl-3′-(4-morpholinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 3674-[(3-chloro-3′-{[(2-hydroxyethyl)amino]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 3684-{(3-chloro-5-methyl-3′-[(4-methyl-1-piperazinyl)methyl][1,1′-bipheny]-4-yl}amino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 3694-{[3-chloro-5-methyl-3′-({[3-(4-morpholinyl)propyl]amino}methyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3704-{[3-chloro-5-methyl-3′-(1-piperidinylmethyl)[1,1′-biphenyl]-4-yl]amino}-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 3714-({3-chloro-3′-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1′-biphenyl]-4-yl}amino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl)-3-quinolinecarbonitrile3724-[(3-chloro-3′-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-5-methyl[1,1′-biphenyl]-4-yl)amino]-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 3734-{2-chloro-4-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-6-methylanilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 3744-[2-chloro-6-methyl-4-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)anilino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 3754-[2-chloro-6-methyl-4-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)anilino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 3764-(2-chloro-4-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-6-methylanilino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 3774-{2-chloro-6-methyl-4-[5-(4-morpholinylmethyl)-3-thienyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 3784-(2-chloro-6-methyl-4-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}anilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile3794-(2-chloro-6-methyl-4-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 3804-(2-chloro-6-methyl-4-[5-(1-piperidinylmethyl)-3-thienyl]anilino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 3814-(2-chloro-4-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-6-methylanilino)-7-(5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile3824-[2-chloro-4-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-6-methylanilino]-7-{5-([4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 3834-[(3-chloro-4-phenoxyphenyl)amino]-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3844-[(3-chloro-4-phenoxyphenyl)amino]-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 3854-[(3-chloro-4-phenoxyphenyl)amino]-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 3864-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3874-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 3884-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{((4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 3894-[(3-chloro-4-phenoxyphenyl)amino]-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 3904-[(3-chloro-4-phenoxyphenyl)amino]-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 3914-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3924-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 3934-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 3944-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 3954-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 3964-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile 3974-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-{[2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 3984-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 3994-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 4004-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile 4014-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 4024-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinocarbonitrile 4034-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl-2-thienyl]-3-quinolinecarbonitrile 4044-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 4054-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile 4064-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile 4074-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 4084-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl)-3-quinolinecarbonitrile 4094-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4104-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile411 4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 4124-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 4134-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 4144-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 4154-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 4164-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4174-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 4184-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 4194-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4204-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 4214-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-{[(3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile422 4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 4234-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4244-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4254-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 4264-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4274-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4284-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4294-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4304-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 4314-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 4324-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4334-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 4344-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4354-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4364-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 4374-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 4384-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 4394-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 4404-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 4414-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 4424-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile 4434-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 4444-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 4454-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 4464-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 4474-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile4484-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 4494-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-thienyl)-3-quinolinecarbonitrile 4504-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 4514-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile 4524-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 4534-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4544-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile4554-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 4564-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 4574-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 4584-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 4594-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 4604-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4614-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 4624-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 4634-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 4644-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 4654-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 4664-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4674-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 4684-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4694-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4704-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 4714-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4724-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4734-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4744-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile 4754-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4764-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 4774-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4784-{[4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4794-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 480 4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4814-{[4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4824-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl}-3-quinolinecarbonitrile 4837-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile 4844-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 4854-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile 4867-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile 4874-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 4884-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4894-{[4-(3-furylmethyl)phenyl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4904-{[4-(3-furylmethyl)phenyl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile 491 4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 4924-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile 4934-{[4-(3-furylmethyl)phenyl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 4947-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile 4954-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile 4964-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile 4977-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile 4984-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile 4994-{[4-(3-furylmethyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile500 4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile 5014-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 5024-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidlnyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 5034-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 5044-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 5054-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 5064-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile 5074-{[4-(3-furylmethyl)phenyl]amino}-7-[5-{[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile 5084-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile 5097-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile 5104-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile 5114-(2,4-dichloro-5-methoxyanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile 5124-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 5134-(2,4-dichloro-5-methoxyanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 5144-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile 5154-(2,4-dichloro-5-methoxyanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile 5164-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 5174-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 5184-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile 5194-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 5204-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 5214-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile 5224-(2,4-dichloro-5-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile 5234-(2,4-dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile 5244-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile 5254-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidlnyl]methyl}-2-thienyl)-3-quinolinecarbonitrile 5264-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile 5274-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile5284-(2,4-dichloro-5-methoxyanilino)-7-(5-}[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile 5294-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl)-3-quinolinecarbonitrile 5304-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile 5314-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile532 4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile 5334-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile 5344-(2,4-dichloro-5-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile535 4-(2,4-dichloro-5-methoxyanilino)-7-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl]-3-quinolinecarbonitrile 5367-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5377-[4-(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5387-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5397-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5407-[4-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5417-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5427-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5437-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5447-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5457-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5467-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5477-[3-(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5487-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5497-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5507-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5517-[3-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5527-((3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5537-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5547-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5557-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5567-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5577-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5587-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5597-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5607-[5-(4-morpholinylmethyl)-3-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5617-(5-[(2-hydroxyethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5627-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5637-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5647-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5657-(5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5667-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile 5677-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile

What is claimed is:
 1. A compound of Formula (I) represented by thestructure:

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, (C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, (C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R^(5, —R) ¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substituted,or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein X is —NH—, —NR⁵, or —O— or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1, wherein T is N and Z is carbon, nis 0 and X is —NH— or a pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 1, wherein T is N, Z is carbon, X is —NH—, n is 0 andR¹ is aryl or a pharmaceutically acceptable salt thereof.
 5. A method oftreating, inhibiting the growth of, or eradicating neoplasms in a mammalin need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (1) having the structure:

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 hetetoatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—; —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹²—CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ling system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R^(15, —(C(R)⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)COR¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 5 wherein the neoplasm is selected from the group consisting ofbreast, kidney, bladder, mouth, larynx, esophagus, stomach, colon,ovary, lung, pancreas, skin, liver, prostate and brain.
 7. The method ofclaim 5 wherein the neoplasm expresses Src or wherein the neoplasmdepends at least in part on the Src pathway.
 8. The method of claim 5wherein the neoplasm expresses raf or wherein the neoplasm depends atleast in part on the raf pathway.
 9. The method of claim 5 wherein theneoplasm expresses EGFr, erbB-2, erbB-3 or erbB-4 or wherein theneoplasm depends at least in part on an EGFr, erbB-2, erbB-3 or erbB-4pathway.
 10. The method of claim 5 wherein the neoplasm expresses KDR orflt-1 or wherein the neoplasm depends at least in part on a KDR or flt-1pathway.
 11. The method of claim 5 wherein the neoplasm expresses PDGFror wherein the neoplasm depends at least in part on the PDGFr pathway.12. The method of claim 5 wherein the neoplasm expresses FGFr or whereinthe neoplasm depends at least in part on the FGFr pathway.
 13. Themethod of claim 5 wherein the neoplasm expresses tie-1 or tie-2 orwherein the neoplasm depends at least in part on a tie-1 or tie-2pathway.
 14. The method of claim 5 wherein the neoplasm expresses EPH orwherein the neoplasm depends at least in part on the EPH pathway. 15.The method of claim 5 wherein the neoplasm expresses a non-receptortyrosine kinase including Abl, Jak, Fak, Syk or Csk or wherein theneoplasm depends at least in part on a Abl, Jak, Fak, Syk or Cskpathway.
 16. The method of claim 5 wherein the neoplasm expresses mek orerk or wherein the neoplasm depends at least in part on the MAPKpathway.
 17. The method of claim 5 wherein the neoplasm expresses acyclin dependent kinase or wherein the neoplasm depends at least in parton a cyclin dependent kinase pathway.
 18. The method of claim 5 whereinthe neoplasm expresses a Src family kinase including Yes, Lck or Lyn orwherein the neoplasm depends at least in part on a Src family kinasepathway.
 19. The method of claim 5 wherein the neoplasm expresses PKA,PKB or PKC or wherein the neoplasm depends at least in part on a PKA,PKB or PKC pathway.
 20. A method of treating, inhibiting the progressionof, or eradicating polycystic kidney disease in a mammal in need thereofwhich comprises administering to said mammal an effective amount of acompound of Formula (1) having the structure:

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR, —Q, —S(O)_(m)R,—NHSO₂R, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)(OR¹⁰,—(C(R⁵)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p),OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NH¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R¹⁰)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, CONHR¹⁰, —COR¹⁰,—C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷R⁵,—NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q,—OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵,—NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵,—C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂,—R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and—R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl group of 1to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰OR¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 21. A method of treating,inhibiting, or eradicating colonic polyps in a mammal in need thereofwhich comprises providing to said mammal an effective amount of acompound of Formula (1) having the structure,

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁷NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or S(O)_(m); R³ is selected from alkenyl of 2 to6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹²—CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONHR₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO,H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰), —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —ROC(O)NH₂, —ROC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J; provided that when R¹² is N(O), R¹³R¹⁴ and n is 1, R¹³or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p))NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p))NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶ NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 22. A method of treatinga disease or inhibiting a disease state whose etiology is at least inpart caused by a defect in a signaling pathway upstream from a proteinkinase; by overexpression of a protein kinase; or by a dysregulatedprotein kinase in a mammal in need thereof which comprises providingsaid mammal an effective amount of a compound of Formula (1),

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—, n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶H, —R⁶R, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹² and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹, —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷R⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶C(O)NHR⁵and —R⁶C(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)⁷ R¹³R¹⁴ and n is 1, R¹³or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 23. A method ofinhibiting the biological effects of a deregulated protein kinase in amammal which comprises administering to said mammal an effective amountof a compound of Formula (1),

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NH⁵R, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂), —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁵)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R,—R⁶OC(O)NH₂, —R⁶C(O)NHR⁵ and —R⁶C(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶H, —R⁶R⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶C(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition for treating or inhibiting disease in a mammal characterizedby abnormal growth of cells which comprises administering to a mammal inneed thereof an effective amount of a compound of Formula (1) having thestructure,

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)R¹²,

G is —NH—, —NR¹⁰—, —O— or S(O)_(m)—; R³ is selected from alkenyl of 2 to6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(PR⁹)₂)_(p)OR¹⁰,—G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ringsystem having 8 to 20 atoms containing 1 to 4 heteroatoms which may bethe same or different selected from N, O and S wherein the bicyclicheteroaryl ring system may be optionally substituted with 1 to 4substituents which may be the same or different selected from —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)O, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰,—(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰,—G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; R⁴ is selected from—(C(R⁹)₂)_(r)H, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹²—CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkenyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 13-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰,—CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S wherein the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)(NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶H, —R⁶R⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O), R¹³R¹⁴ or—N⁺(R¹⁰R¹³R⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R₅;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)(OR¹⁰, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶ or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)₂)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 25. A method of treatingor inhibiting the progression of restenosis in a mammal in need thereofwhich comprises providing to said mammal an effective amount of a PDGFrkinase inhibitor of Formula (1) having the structure,

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, (isand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ting of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR¹⁰C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —N—, —NR¹⁰—, —O—or —S(O)_(m)—; R³ is selected from alkenyl of 2 to6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)R_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they arc attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(p)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 26. A method of treating,inhibiting or eradicating autoimmune diseases which include rheumatoidarthritis, sepsis and transplant rejection in a mammal in need thereofwhich comprises providing to said mammal an effective amount of Zap-70or Lck kinase inhibitor of Formula (1), having the structure,

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m), —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷R⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R),—CONHR¹⁰, —COR¹⁰), —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹ ², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p),R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶C(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NHR₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂,—NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH,—OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵,—OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NR⁵, —C(O)Q, —R⁶C(O)H,—R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q,—R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; R⁹ is independently—H, —F or —R⁵; R¹⁰ is an alkyl group of 1 to 12 carbon atoms, preferredis 1 to 6 carbon atoms; R¹¹ is a cycloalkyl group of 3 to 10 carbonatoms: R¹² is —N(O)_(n)R¹³R¹⁴ or —N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that whenR¹² is N(O)_(n)R¹³R¹⁴ and n is 1, R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ areindependently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl-R¹⁵, —(C(R⁹)₂)_(q)heteroaryl-R¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷,—(C(R⁹)₂)_(p)S(O)_(m)R¹⁶, —(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶and —(C(R⁹)₂)_(p)C(O)R¹⁵; further provided that R¹³ and R¹⁴ mayoptionally be taken together with the nitrogen to which they areattached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ringoptionally substituted on either nitrogen or carbon by one or moreselected from the group, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)arylR¹⁵,—(C(R⁹)₂)_(q)heteroarylR¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(q)CO₂R¹⁶, —(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵;or optionally substituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶,—(C(R⁷)₂)_(q)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionallysubstituted on nitrogen by —(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and—(C(R⁹)₂)_(p)S(O)_(m)R¹⁶; R¹⁵ is independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl,—(C(R⁹)₂)_(q)heterocyclyl, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰,—(C(R⁹)₂)_(q)S(O)R¹⁰, —(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰,—(C(R⁹)₂)_(q)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and—(C(R⁹)₂)_(q)CONH₂; R¹⁶ and R¹⁷ are independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl,—(C(R⁹)₂)_(q)heterocyclyl, —(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰,—(C(R⁹)₂)_(p)NH₂, —(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰,—(C(R⁹)₂)_(p)S(O)_(m)R¹, —(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰,—(C(R⁹)₂)_(p)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and—(C(R⁹)₂)_(p)CONH₂; R¹⁸ is independently selected from the groupconsisting of —H, -aryl, —R⁵, —R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that,the 7-position is substituted or a pharmaceutically acceptable saltthereof.
 27. A method of treating, inhibiting or eradicating viralinfections in a mammal in need thereof which comprises providing to saidmammal an effective amount of UL-97 kinase inhibitor of Formula (1)having the structure,

wherein: X is —NH—, —NR⁵—, —O—, or —S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶C(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O,—(C(R⁹)₂)_(q)S(O)_(m)—, —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ling of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR⁷OR⁵, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is—NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2 to6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R⁵, —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹²; —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰), —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionally substitutedwith one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂,—CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionally substitutedwith 1 to 4 substituents which may be the same or different selectedfrom —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H,—CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR^(10, —(C(R) ⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S wherein the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —COR¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(q)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R¹², —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶H, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR¹⁰H, —OR⁷R⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R¹⁰C(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O),aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl-R¹⁵,—(C(R⁹)₂)_(q)heteroaryl-R¹⁵, —(C(R⁹)₂)_(q)heterocyclyl-R¹⁵,—(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶,—(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶ and —(C(R⁹)₂)_(p)C(O)R¹⁵;further provided that R¹³ and R¹⁴ may optionally be taken together withthe nitrogen to which they are attached forming a heterocyclyl,heteroaryl or bicyclyl heteroaryl ring optionally substituted on eithernitrogen or carbon by one or more selected from the group, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)arylR¹⁵, —(C(R⁹)₂)_(q)heteroarylR¹⁵,—(C(R⁹)₂)_(q)heterocyclylR¹⁵, —(C(R⁹)₂)_(q)CO₂R¹⁶,—(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵; or optionallysubstituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶, —(C(R⁷)₂)_(q)NR¹⁶R¹⁷,and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionally substituted on nitrogen by—(C(R⁹)₂)_(q)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(p)S(O)_(m)R¹⁶;R¹⁵ is independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰, —(C(R⁹)₂)_(q)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰, —(C(R⁹)₂)_(q)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and —(C(R⁹)₂)_(q)CONH₂; R¹⁶ andR¹⁷ are independently selected from a group consisting of —H, —R⁵, —R¹¹,—(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl, —(C(R⁹)₂)_(q)heterocyclyl,—(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(p)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰, —(C(R⁹)₂)_(p)S(O)_(m)R¹⁰,—(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰, —(C(R⁹)₂)_(p)CONR¹⁰R¹⁰,—(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and —(C(R⁹)₂)_(p)CONH₂; R¹⁸ isindependently selected from the group consisting of —H, -aryl, —R⁵,—R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that, the 7-position is substitutedor a pharmaceutically acceptable salt thereof.
 28. A method of treatingor inhibiting the progression of osteoporosis in a mammal in needthereof which comprises providing to said mammal an effective amount ofSrc kinase inhibitor of Formula (1) having the structure,

wherein: X is —NH—, —NR⁵—, —O—, or o—S(O)_(m)—; n is an integer of 0 or1; m is an integer of 0 to 2; q is an integer of 0 to 5; p is an integerof 2 to 5; s is an integer of 0 to 5; r is an integer of 0 to 5; J ishalogen; A is absent; T is N and Z is carbon; R¹ is a heteroaryl ringhaving 6 atoms containing 1 to 3 heteroatoms, 1 of which is N, orparticularly 1 or 2 heteroatoms which may be the same or different,selected from N, O and S wherein the heteroaryl ring may be optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵,—NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —R⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵,—OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —R⁶C(O)R⁵, —NHR⁶C(O)R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q and YR⁸ groups wherein Y is independentlyselected from —C(O)—, —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —NHSO₂—,—SO₂NH—, —C(OH)H—, —O(C(R⁹)₂)_(q)—, —S(O)_(m)(C(R⁹)₂)_(q)—,—NH(C(R⁹)₂)_(q)—, —NR¹⁰(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)—, —(C(R⁹)₂)_(q)O—,—(C(R⁹)₂)_(q)S(O)_(m), —(C(R⁹)₂)_(q)NH—, —(C(R⁹)₂)_(q)NR¹⁰—, —C≡C—, cisand trans —CH═CH— and cycloalkyl of 3 to 10 carbon atoms; Q is —NR⁵R⁵and further provided that when each R⁵ is independently selected fromalkyl and alkenyl, R⁵R⁵ may optionally be taken together with thenitrogen atom to which they are attached forming a heterocyclyl ring of3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms whichmay be the same or different selected from N, O and S; R^(2a), R^(2b),and R^(2c), are each, independently selected from —H, -aryl, —CH₂aryl,—Oaryl, —S(O)_(m)aryl, —J, —NO₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹,—OR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶SH, —R⁶S(O)_(m)R⁵, —OR⁷OH, —OR¹⁰R, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, R⁶C(O)R⁵, —R⁶C(O)OR⁵, —R⁶C(O)OH,—R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶OC(O)NH₂,—R⁶OC(O)NHR⁵, —R⁶OC(O)Q, —G—(C(R⁹)₂)_(p)—R¹², —(C(R⁹)₂)_(q)—R¹²,

G is —NH—, —NR¹⁰—, —O— or —S(O)_(m)—; R³ is selected from alkenyl of 2to 6 carbon atoms, optionally substituted with one or more of —R¹⁰,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; alkynyl of2 to 6 carbon atoms, optionally substituted with one or more of —R,—(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂,—CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H,—G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and —G(C(R⁹)₂)_(p)OH; aryl of 6to 12 carbon atoms optionally substituted with 1 to 4 substituents whichmay be the same or different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be thesame or different, selected from N, O and S where the heteroaryl ringmay be optionally substituted with 1 to 4 substituents which may be thesame or different selected from —R¹, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20atoms containing 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁴ is selected from —(C(R⁹)₂)_(r)H, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkenyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)₅R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; alkynyl of 2 to 6 carbon atoms, optionallysubstituted with one or more of —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO,1,3-dioxolane, —NO₂, —CN, —CO₂H, —CONHR₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰,—(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹²,and —G(C(R⁹)₂)_(p)OH; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane, —NO₂, —CN,—CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a heteroaryl ring having 5 or 6 atoms containing 1 to4 heteroatoms or particularly 1 or 2 heteroatoms which may be the sameor different, selected from N, O and S wherein the heteroaryl ring maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —R¹⁰, —(C(R⁹)₂)_(s)R¹², —CHO, 1,3-dioxolane,—NO₂, —CN, —CO₂H, —CONH₂, —CO₂R¹⁰, —CONHR¹⁰, —COR¹⁰, —(C(R⁹)₂)_(q)OH,—(C(R⁹)₂)_(q)OR¹⁰, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)J, —(C(R⁹)₂)_(q)NH₂,—(C(R⁹)₂)_(r)H, —G(C(R⁹)₂)_(p)OR¹⁰, —G(C(R⁹)₂)_(p)R¹², and—G(C(R⁹)₂)_(p)OH; R⁵ is a monovalent group independently selected fromalkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenylof 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁶ is adivalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R⁷ is a divalentalkyl group of 2 to 6 carbon atoms; R⁸ is a cycloalkyl ring of 3 to 10carbon atoms that may optionally be substituted with one or more alkylgroups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionallysubstituted with 1 to 4 substituents which may be the same or differentselected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl, —S(O)_(m)aryl, —J,—NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃,—OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵, —NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹,—R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R, —NHR⁷OH,—NHR⁷OR⁵, —N(R⁵)R⁷OH, —R⁶R⁷, —N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q,—N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵, —N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂,—OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵, —NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵,—NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R,—R⁶C(O)OH, —R⁶C(O)OR⁵, —R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵,—R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵ and —R⁶OC(O)Q; a heteroaryl ring having 5 or 6atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatomswhich may be the same or different, selected from N, O and S wherein theheteroaryl ring may be optionally substituted with 1 to 4 substituentswhich may be the same or different selected from —H, -aryl, —CH₂aryl,—NHaryl, —Oaryl, —S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃,—COOH, —CONH₂, —NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q,—S(O)_(m)R⁵, —NHSO₂R, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶H, —R⁶OR⁵, —R⁶NH₂,—R⁶NHR⁵, —R⁶Q, —R⁶SH, —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁷OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —R⁶R¹², —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵,—C(O)OR⁵, —C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R, —R⁶OC(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atomscontaining 1 to 4 heteroatoms which may be the same or differentselected from N, O and S wherein the bicyclic heteroaryl ring system maybe optionally substituted with 1 to 4 substituents which may be the sameor different selected from —H, -aryl, —CH₂aryl, —NHaryl, —Oaryl,—S(O)_(m)aryl, —J, —NO₂, —NH₂, —OH, —SH, —CN, —N₃, —COOH, —CONH₂,—NHC(O)NH₂, —C(O)H, —CF₃, —OCF₃, —R⁵, —OR⁵, —NHR⁵, —Q, —S(O)_(m)R⁵,—NHSO₂R⁵, —R¹¹, —OR¹¹, —NHR¹¹, —R⁶OH, —R⁶OR⁵, —R⁶NH₂, —R⁶NHR⁵, —R⁶Q,—R⁶SH, —R⁶R¹², —R⁶S(O)_(m)R⁵, —NHR⁷OH, —NHR⁷OR⁵, —N(R⁵)R⁶OH,—N(R⁵)R⁷OR⁵, —NHR⁷NH₂, —NHR⁷NHR⁵, —NHR⁷Q, —N(R⁵)R⁷NH₂, —N(R⁵)R⁷NHR⁵,—N(R⁵)R⁷Q, —OR⁷OH, —OR⁷OR⁵, —OR⁷NH₂, —OR⁷NHR⁵, —OR⁷Q, —OC(O)R⁵,—NHC(O)R⁵, —NHC(O)NHR⁵, —OR⁶C(O)R⁵, —NHR⁶C(O)R⁵, —C(O)R⁵, —C(O)OR⁵,—C(O)NHR⁵, —C(O)Q, —R⁶C(O)H, —R⁶C(O)R⁵, —R⁶C(O)OH, —R⁶C(O)OR⁵,—R⁶C(O)NH₂, —R⁶C(O)NHR⁵, —R⁶C(O)Q, —R⁶OC(O)R⁵, —R⁶C(O)NH₂, —R⁶OC(O)NHR⁵and —R⁶OC(O)Q; R⁹ is independently —H, —F or —R⁵; R¹⁰ is an alkyl groupof 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms; R¹¹ is acycloalkyl group of 3 to 10 carbon atoms; R¹² is —N(O)_(n)R¹³R¹⁴ or—N⁺(R¹⁰R¹³R¹⁴)J⁻; provided that when R¹² is N(O)_(n)R¹³R¹⁴ and n is 1,R¹³ or R¹⁴ are not H; R¹³ and R¹⁴ are independently selected from agroup consisting of —(C(R⁹)₂)_(q)aryl-R¹⁵, —(C(R⁹)₂)_(q)heteroaryl-R¹⁵,—(C(R⁹)₂)_(q)heterocyclyl-R¹⁵, —(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷,—(C(R⁹)₂)_(p)S(O)_(m)R¹⁶, —(C(R⁹)₂)_(p)CO₂R¹⁶, —(C(R⁹)₂)_(p)C(O)NHR¹⁶and —(C(R⁹)₂)_(p)C(O)R¹⁵; further provided that R¹³ and R¹⁴ mayoptionally be taken together with the nitrogen to which they areattached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ringoptionally substituted on either nitrogen or carbon by one or moreselected from the group, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)arylR¹⁵,—(C(R⁹)₂)_(q)heteroarylR¹⁵, —(C(R⁹)₂)_(q)heterocyclylR¹⁵,—(C(R⁹)₂)_(q)CO₂R¹⁶, —(C(R⁹)₂)_(q)C(O)NHR¹⁶, and —(C(R⁹)₂)_(q)C(O)R¹⁵;or optionally substituted on carbon by —F, —(C(R⁷)₂)_(q)OR¹⁶,—(C(R⁷)₂)_(q)NR¹⁶R¹⁷, and —(C(R⁹)₂)_(q)S(O)_(m)R¹⁶; or optionallysubstituted on nitrogen by —(C(R⁹)₂)_(p)OR¹⁶, —(C(R⁹)₂)_(p)NR¹⁶R¹⁷, and—(C(R⁹)₂)_(p)S(O)_(m)R¹⁶; R¹⁵ is independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl,—(C(R⁹)₂)_(q)heterocyclyl, —(C(R⁹)₂)_(q)OH, —(C(R⁹)₂)_(q)OR¹⁰,—(C(R⁹)₂)_(q)NH₂, —(C(R⁹)₂)_(q)NHR¹⁰, —(C(R⁹)₂)_(q)R¹⁰,—(C(R⁹)₂)_(q)S(O)_(m)R¹⁰, —(C(R⁹)₂)_(q)CO₂R¹⁰, —(C(R⁹)₂)_(q)CONHR¹⁰,—(C(R⁹)₂)_(q)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(q)COR¹⁰, —(C(R⁹)₂)_(q)CO₂H, and—(C(R⁹)₂)_(q)CONH₂; R¹⁶ and R¹⁷ are independently selected from a groupconsisting of —H, —R⁵, —R¹¹, —(C(R⁹)₂)_(q)aryl, —(C(R⁹)₂)_(q)heteroaryl,—(C(R⁹)₂)_(q)heterocyclyl, —(C(R⁹)₂)_(p)OH, —(C(R⁹)₂)_(p)OR¹⁰,—(C(R⁹)₂)_(p)NH₂, —(C(R⁹)₂)_(r)NHR¹⁰, —(C(R⁹)₂)_(p)NR¹⁰R¹⁰,—(C(R⁹)₂)_(p)S(O)_(m)R¹⁰, —(C(R⁹)₂)_(p)CO₂R¹⁰, —(C(R⁹)₂)_(p)CONHR¹⁰,—(C(R⁹)₂)_(p)CONR¹⁰R¹⁰, —(C(R⁹)₂)_(p)COR¹⁰, —(C(R⁹)₂)_(p)CO₂H, and—(C(R⁹)₂)_(p)CONH₂; R¹⁸ is independently selected from the groupconsisting of —H, -aryl, —R⁵, —R⁶NH₂, —R⁶NHR⁵ and —R⁶Q; provided that,the 7-position is substituted or a pharmaceutically acceptable saltthereof.